rab7: roles in membrane trafﬁcking and disease · biosci. rep. (2009) / 29 / 193–209 (printed...

Biosci. Rep. (2009) / 29 / 193–209 (Printed in Great Britain) / doi 10.1042/BSR20090032

Rab7: roles in membrane trafficking and diseaseMing ZHANG, Li CHEN, Shicong WANG and Tuanlao WANG1

Institute for Biomedical Research, Xiamen University, Xiamen, Fujian, 361005, People’s Republic of China

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SynopsisThe endocytosis pathway controls multiple cellular and physiological events. The lysosome is the destination ofnewly synthesized lysosomal hydrolytic enzymes. Internalized molecules or particles are delivered to the lysosomefor degradation through sequential transport along the endocytic pathway. The endocytic pathway is also emergingas a signalling platform, in addition to the well-known role of the plasma membrane for signalling. Rab7 is a lateendosome-/lysosome-associated small GTPase, perhaps the only lysosomal Rab protein identified to date. Rab7plays critical roles in the endocytic processes. Through interaction with its partners (including upstream regulatorsand downstream effectors), Rab7 participates in multiple regulation mechanisms in endosomal sorting, biogenesis oflysosome [or LRO (lysosome-related organelle)] and phagocytosis. These processes are closely related to substratesdegradation, antigen presentation, cell signalling, cell survival and microbial pathogen infection. Consistently, muta-tions or dysfunctions of Rab7 result in traffic disorders, which cause various diseases, such as neuropathy, cancerand lipid metabolism disease. Rab7 also plays important roles in microbial pathogen infection and survival, as wellas in participating in the life cycle of viruses. Here, we give a brief review on the central role of Rab7 in endosomaltraffic and summarize the studies focusing on the participation of Rab7 in disease pathogenesis. The underlyingmechanism governed by Rab7 and its partners will also be discussed.

Key words: disease, endocytosis, membrane trafficking, pathogen infection, Rab7, virus

INTRODUCTION

The Rab proteins belong to the Ras small GTPase superfam-ily. During the past two decades, a large amount of literaturehas addressed the properties and functions of the Rab proteinsand established Rab GTPases as master regulators in membranetrafficking [1–5]. Rab exerts its function through the GTPasecycle. Newly synthesized Rab is recognized by REP (Rab es-cort protein) and transferred to RabGGT (Rab geranylgeranyltransferase) for prenylation, the prenylated Rab then goes on tothe GTPase cycle. In the cytosoplasm, GDP-bound Rab is as-sociated with GDI (GDP dissociation inhibitor), and GDF (GDIdisplacement factor) recruits Rab to the membrane where GEF(guanine-nucleotide-exchange factor) converts it into the GTP-bound active form, which interacts with downstream effectors toexert its biological functions. GTP hydrolysis of Rab convertsit back into the GDP-bound form, which is generally facilitated

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Abbreviations used: BCV, Brucella-containing vacuole; BMDC, bone-marrow-derived cell; CMT2B, Charcot–Marie–Tooth syndrome type 2B; DENV, Dengue virus; EEA1, early endosomeantigen 1; EGF, epidermal growth factor; EGFR, EGF receptor; ER, endoplasmic reticulum; ESCRT, endosomal sorting complex required for transport; FSD, functional secretory domain;GAP, GTPase-activation protein; GDI, GDP dissociation inhibitor; GDF, GDI displacement factor; GEF, guanine-nucleotide-exchange factor; HOPS, homotypic fusion and protein sorting;HPS, Hermanskey–Pudlak syndrome; HSAN, hereditary sensory and autonomic neuropathy; Lamp, lysosome-associated membrane protein; LDL, low-density lipoprotein;MVB, multivesicular body; NGF, nerve growth factor; NPC, Niemann–Pick type C; OSBP, oxysterol-binding protein; ORP1L, OSBP-related protein 1; PI3K, phosphoinositide 3-kinase;PV, parasitophorous vacuole; RabGGT, Rab geranylgeranyl transferase; RB, ruffled border; RBG-3, RabGAP initially supposed to target Rab3; REP, Rab escort protein; RIDα, receptorinternalization and degradation α; RILP, Rab7-interacting lysosomal protein; SCV, Salmonella-containing vacuole; SFV, Semliki Forest virus; Sif, Salmonella-induced filament; SLSD,sphingolipid storage disease; SNX1/2, sorting nexin 1/2; TrkA, tropomyosin receptor tyrosine kinase A; TRP, tyrosinase-related protein; UVRAG, UV-irradiation resistance-associatedgene product; VEEV, Venezuelan equine encephalitis virus; (h)Vps, (human) vacuolar protein sorting; VSV, vesicular stomatitis virus.1To whom correspondence should be addressed (email [email protected]).

by GAP (GTPase-activation protein). It has been indicated thatRab proteins regulate not only membrane trafficking, but also cellsignalling, cell growth, cell survival and development [6,7]. Rabproteins and their associated regulators or effectors have beenimplicated in many diseases, such as cancer, pigmentation dis-order, neuropathy and lipid metabolism disorders. Genetic muta-tions and abnormal expression of Rab proteins or their partnersare closely linked to disease pathogenesis [8–13]. Furthermore,pathogens usually hijack Rab-mediated trafficking machineriesin host cells for infection and survival [10,14]. Therefore it willbe very useful to develop therapeutic strategies targeting Rab ormodulating Rab-mediated membrane traffic [15].

For the Rab family of GTPases, approx. 70 members have beenidentified in mammals. Rab7 is one of Rab proteins which hasbeen investigated extensively. The extensive studies have revealedthat Rab7 is a central factor in endosomal membrane traffick-ing. Trafficking disorders, resulting from mutation or dysfunc-tion of Rab7, can cause human diseases, and the Rab7-mediated

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M. Zhang and others

membrane traffic process is linked to pathogen infection andsurvival. In the following sections, we give a brief review onthe functions of Rab7, summarize the involvement of Rab7 indisease pathogenesis and discuss the possible underlying mech-anisms that are regulated by Rab7.

RAB7: CENTRAL ROLES IN THEENDOCYTIC PATHWAY

Rab7 is associated primarily with late endosomal structures, andperhaps it is the only lysosomal Rab protein found to date[16–20].The functions of Rab7 have been investigated extensively. Fenget al. [21] indicated that the dominant-negative mutants Rab7-T22N and Rab7-N125I blocked trafficking of the VSV (vesicularstomatitis virus) G protein from the early endosome to the lateendosome, without affecting its internalization from the surface.In addition, the Rab7 mutants caused accumulation of cathepsinD and the cation-independent mannose-6-phosphate receptor inearly endocytic compartments, and inhibited the maturation pro-cess of cathepsin D [22]. Vitelli et al. [23] examined the effects ofRab7 on degradation of internalized LDLs (low-density lipopro-teins) and found that dominant-negative forms of Rab7 inhibitedLDL degradation. These studies conclude that Rab7 serves as akey factor in regulating transport of lysosome-destined enzymesand internalized surface proteins to the lysosome through theendocytic pathway.

It has been observed that Rab proteins act in concert withtheir special tethering complexes to determine a unique mem-brane identity, which generates various Rab-defined membranedomains [2,4,24,25]. Within the endocytic pathway, many Rabproteins localize to endocytic compartments: Rab4, Rab5, Rab11,Rab22 and Rab25 are primarily associated with the early and re-cycling endosomes [26–30]; Rab9 and Rab7 are localized to lateendosome [31,32]. Rab7 is additionally localized to the lyso-some and was thus characterized also as a lysosome-associatedRab protein [16]. Rab5 and its effectors, rabaptin-5, Rabex-5, EEA1 (early endosome antigen 1), Rabenosyn-5, hVps34(human vacuolar protein sorting 34)/p150 may be defined as anearly endosomal membrane domain [33]. Rab4 and Rab11 havebeen shown to associate with the exocyst complex at the recyc-ling endosomal membrane [34]. Rab7 and its effectors are emer-ging to generate Rab7-defined membrane domains, playing cent-ral roles in the late endocytic pathway (Figure 1). Rab7-definedmembrane domains include late endosome, intermediate hybridsof late endosomes–lysosomes, and the lysosome. Rab7 regulateslate endosomal membrane fusion and trafficking mediated by atethering complex, which is carried out by the HOPS (homotypicfusion and protein sorting; also refers to class C Vps protein)complex. The HOPS complex consists of Vps11, Vps16, Vps18,Vps33, Vps39 and Vps41. Vps39 binds to Rab7 and exhibits GEFactivity for Rab7. Vps33 is a munc-1-like protein, which can as-sociate with the endosomal SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) protein to

regulate membrane fusion, thus Rab7 interacts with the HOPScomplex and is recruited to the endosomal membrane to regulatevesicle fusion [this process may also require phosphoinositidesregulated by PI3K (phosphoinositide 3-kinase)/hVps34] [20,35–39]. The distribution and movement of the late endosome/lyso-some is regulated by interaction of Rab7—RILP–dynein–dynactin (where RILP is Rab7-interacting lysosomal protein)[40,41].

Rab5-defined early endosomal membrane domains and Rab7-defined late endosomal/lysosomal membrane domains do notwork separately, but sequentially and dynamically to co-operatein the endocytic pathway. Along the endocytic pathway, cargosare internalized from the plasma membrane and transported tothe early endosome. At the early endosome, cargos are sortedto different destinations: the recycling endosome, the late endo-some and lysosome or the Golgi apparatus (Figure 1), in which theRab cascade determines the unique trafficking pathway [24,42].Membrane trafficking from the early endosome to the late endo-some is determined by the recruitment of Rab5 to earlyendosomes and, sequentially, acquisition of Rab7 followed byloss of Rab5 in the late endosomes. By employing live-cell ima-ging technology, Rink et al. [38] observed the conversion of Rabfrom Rab5 into Rab7 in endosomal membrane dynamics duringthe transport from the early endosome to the late endosome. Thedissociation of Rab5 and subsequent recruitment of Rab7 wereregulated by the HOPS complex. The HOPS complex may play acritical role in this Rab cascade, since it is also an effector of Rab5GTPase [43]. The sequential action of Rab5 and Rab7 in endo-cytosis and endosomal sorting/maturation was also observed inXenopus oocytes [44] and in axonal retrograde transport in neur-ons [45]. Rab7, working co-operatively with Rab5, was invest-igated in the recruitment of the retromer complex [comprisingSNX1/2 (sorting nexin 1/2), Vps26, Vps29 and Vps35]. Theinteraction between Rab7 and the retromer complex has beenstudied in the protozoan parasite Entamoeba histolytica [46].Recently, the works by Rojas et al. [47] offered a possible mech-anism for Rab5 and Rab7 to regulate retromer recruitment andfunction. In this model, Rab5 interacted with PI3K and recruitedSNX1/2 to membrane, whereas Rab7 recruited the retromer corecomplex Vps26–Vps29–Vps35 through direct interaction withVps26. The following interaction of SNX1/2 with Vps26/29/35mediates cargo transport. Unexpectedly, the role of RILP in thisprocess was not examined, and the HOPS complex may alsoplay a role in this regulation. The involvement of Rab7 in ret-romer regulation suggests that Rab7 also participates in retro-grade transport between the endosomes and the Golgi apparatus.

The functions of Rab7 are regulated via the GTPase cycle andits partners, including upstream regulators and specific down-stream effectors, as shown in Figure 2. So far, there are noupstream regulators, such as REP, RabGGT, GDI or GDF, identi-fied specifically for Rab7, and Rab7 may share these common reg-ulators with other Rab proteins. For example, Rab7 prenylationis regulated by REP-1 [48]. Similar to other GTPases, Rab7 mayhave its specific GAP and GEF. The yeast protein Gyp7p and itsmammalian homologue TBC1D15 [a TBC (Tre2/Bub2/Cdc16)-domain-containing protein] were identified as GAPs for Ypt7

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194 C©The Authors Journal compilation C©2009 Biochemical Society

Rab7 in membrane trafficking and disease

Figure 1 Rab7 plays central roles in the late endosomal traffic pathwayRab5 interacts with tethering complex (Rab5ex5, Rabaptin5, Rabenosyn5 and EEA1) to regulate early endosomal traffick-ing; Rab4 and Rab11 associate with the exocyst to regulate recycling traffic from the recycling endosome to the plasmamembrane; Rab7 interacts with the HOPS complex and its various effectors to regulate membrane traffic from the earlyendosome to the late endosome, and from late endosome to the lysosome. See the text for further details.

Figure 2 Regulation of Rab7 GTPase and interaction of Rab7 witheffctorsGDP-bound Rab7 can be converted into the GTP-bound active form bya GEF (such as the HOPS complex), which interacts with downstreameffectors to exert its biological functions. GAPs (such as GYP7) facilitateGTP hydrolysis of Rab7 and convert it back into the GDP-bound form.

and Rab7 respectively [49,50]. The HOPS complex exhibits GEFactivity for Rab7 [37,38].

As shown in Table 1, Rab7 interacts with multiple down-stream effectors. RILP is one of the well-studied Rab7 down-stream effectors; the Rab7–RILP interaction is a crucial mechan-ism in regulating endosomal traffic and biogenesis of late endo-somal/lysosomal compartments [40,51]. Overexpression of RILP

caused enlarged Rab7-containing late endosomes/lysosomeswith a peri-nuclear distribution. The truncated form of RILPalso impaired endosomal transport of EGFR (epidermal growthfactor receptor) and LDL receptors [40]. Further investiga-tion revealed that Rab7 regulates lysosomal movement towardsthe MTOC (microtubule-organizing centre) through RILP tointeract with the minus-end-directed motor protein dynein–dynactin complex, with the participation of another Rab7-interacting effector ORP1L [OSBP (oxysterol-binding protein)-related protein 1] [41,52]. RILP can also interact with Vps22and Vps36 to regulate the late endosomal or MVBs (multivesi-cular bodies) degradation pathway [53,54]. Other effectors forRab7 have also been described (Table 1). Rabring7 (Rab7-interacting RING-finger protein) is involved in EGF degrada-tion as an E3 ligase [55]. PI3K/hVps34/p150 forms complexeswith Rab7, suggesting that Rab7 may also regulate PI3K activ-ity and membrane trafficking from the early endosome to thelate endosome [56]. Rab7 can bind to the proteasome α-sub-unit XAPC7 and recruit it to the late endosome. XAPC7 mayserve as a negative regulator for Rab7, since overexpression ofXAPC7 impairs EGFR-mediated endocytosis, which can be res-cued by expressing wild-type Rab7 [57]. Rab7 directly interactswith small GTPase Rac1 to regulate the formation of RBs (ruffledborders) in osteoclasts [58]. Collectively, Rab7 interacts withmultiple effectors and participates in multiple biological events.

Rab7 plays a central role, not only in endosomal traffic,but also in many other cellular and physiological events, suchas growth-factor-mediated cell signalling, nutrient-transportor-mediated nutrient uptake, neurotrophin transport in the axonsof neurons and lipid metabolism. In addition to the normal en-docytic traffic pathway, Rab7 is involved in regulation of some

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M. Zhang and others

Table 1 Partners interacting with Rab7 in mammalian cells

Partner Partner function Reference

RILP Rab7-interacting lysosomal protein involved in late endosomal/lysosomalmorphogenesis; regulates vesicle transport through interaction withdynein–dynactin motor complex.

[40,41,51,52]

Rabring7 Rab7-interacting RING-finger protein; as a E3 ligase which can ubiquitinate itselfand regulate EGFR degradation.

[55]

HOPS complex Homotypic fusion and vacuole protein sorting complex, comprising VPS-11, -16,-18, -33, -39 and -41. A tethering complex that regulates the endosomalmembrane fusion. VPS39 serves as a GEF for Rab7.

[20,35–39]

Retromers The core retromer complex VPS26–VPS29–VPS35 interacts with Rab7 throughVPS26 directly binding to Rab7; regulates the retrograde transport fromendosomes to trans-Golgi network.

[46,47]

ORP1L OSBP (oxysterol-binding protein)-related protein; required for activation ofdynein–dynactin motor, together with Rab7, RILP and βlll spectrin; regulateslate endosome/lysosome organization and late endocytic transport.

[52]

XAPC7 Proteasome α-subunit XAPC7 (PSMA7, HSPC, RC6-1, and C6-I in mammals);overexpression of XAPC7 decreases late endocytic transport.

[57]

Rac1 Ras-like small GTPase that regulates cytoskeleton organization; Rab7 interactswith Rac1 to regulate RB formation in osteoclasts.

[58]

Pleckhm1 Pleckstrin homology domain-containing family M (with RUN domain) member 1;functions in vesicular transport in the osteoclast.

[103]

hVPS34/p150 Human type III PI3K and adaptor regulating endosomal trafficking and cellsignalling by producing phosphatidylinositol-3-phosphate; Rab7 regulates theactivity of hVPS34.

[56]

REP-1 Rab escort protein 1 that presents Rab7 to rab geranylgeranyl transferase. [48]TrkA Receptor-tyrosine kinase A of NGF; Rab7 interacts with TrkA controlling the

endosomal trafficking and neurite outgrowth signaling of TrkA.[76]

TBC1D15 TBC (Tre-2/Bub2/Cdc16) domain-containing protein homologue of GYP7p, a GAPfor Ypt7p in yeast; serves as a GAP for Rab7.

[49,50]

specialized endosomal membrane trafficking, such as maturationof melanosomes, pathogen-induced phagosomes (or vacuoles)and autophagosomes. In the following sections, we will describesome diseases or physiological disorders caused by mutations ordysfunction of Rab7, and how Rab7 and its partners are engagedin infectious diseases caused by microbial pathogens or viruses.

DISEASES CAUSED BY MUTATIONSOR DYSFUNCTION OF RAB7

Rab proteins are master regulators of membrane trafficking. Stud-ies have linked Rab proteins and Rab-regulated traffic to manydiseases [10,13]. For examples, genetic defects in Rab27a andits partner Myo5a cause Griscelli syndrome [59]; mutations inthe upstream regulators of Rab, REP, RabGDI and RabGGT, arelinked to the renal degeneration disease choroidaermia, X-linkedmental retardation and HPS (Hermanskey–Pudlak syndrome) re-spectively [60–62]; abnormal expression of Rab25 is associatedwith the development of ovary and breast cancer [63]. A num-ber of studies have indicated that Rab7 is another important Rabinvolved in disease pathogenesis. Mutations in Rab7 gene ordysfunction of Rab7 and Rab7-interacting effectors may causediseases or physiological disorders (Table 2).

Rab7 in neuropathySeveral Rab proteins are expressed in neurons and glia, and someof them are closely related to neurological functions [64]. Thereare reports showing that defects of Rab5 and Rab7-regulatedlate endocytic traffic are related to neurological diseases, such asAlzheimer’s disease and Down’s syndrome [65]. The direct evid-ence that Rab7 is involved in neuropathy comes from the studieson CMT2B (Charcot–Marie–Tooth syndrome type 2B). Muta-tions in Rab7 are well characterized as genetic defect markers forCMT2B, which is part of a group knowns as the HSNs [hereditarysensory neuropathies; also referred as HSANs (hereditary sens-ory and autonomic neuropathies)]. Patients suffering this defectexhibit progressively neurological disorders with clinical symp-toms of distal sensory loss, muscle weakness and foot ulcerations[66–69]. So far, four mutations in Rab7 have been identified infour different families with CMT2B, and all mutations occur inthe conserved amino-acid residues adjacent to the switch II regionin the C-terminal part of Rab7, including the mutations L129F,K157N, N161T and V162M [70–73].

Recently, the underlying mechanisms for CMT2B due to Rab7mutations have been investigated. Spinosa et al. [74] studied thebiochemical and functional properties of three Rab7 mutants,Rab7-L129F, Rab7-N161T and Rab7-V162M, and found all threemutant forms exhibited lower GTPase activity than the wild-typeform and had a preference for GTP binding, indicating the mu-tant forms of Rab7 are more activated than wild-type Rab7, which

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Table 2 Diseases that may be related to defects in Rab7 or its partnersARC, arthrogryposis-renal dysfunction-cholestasis; MEF, mouse embryonic fibroblast; RNAi, RNA interference.

Disease Patho-mechanism related to Rab7 Reference

Neurological disease

CMT2B Genetic mutations in Rab7 gene at L129F, K157N, N161Tand V162M.

[70–73]

Alzheimer’s disease and Down’s syndrome Late endocytic traffic defects possibly regulated by Rab7and Rab5.

[65]

Cancer and cell survival

Thyroid adenomas Rab7 is overexpressed by cAMP stimulation. [80]

Diffuse peritoneal malignant mesothelioma Rab7 is overexpressed. [79]

Growth-factor-independent survival Inhibition of Rab7 sustains surface nutrient transportorupon growth-factor depletion.

[7,81]

Transformation of p53−/− MEFs Inhibition of Rab7 co-operates with E1A and in theabsence of p53.

[82]

Cell apoptosis RNAi of Rab7 and its down stream effectors: componentsof HOPS complex.

[83,84]

Lipid trafficking disorder

NPC disease Dysfunction of Rab7 results in accumulation ofsphingolipids and cholesterol in late endosomes.

[91–93]

Adult-onset obesity Involvement of Rab7 in tub-1 pathway through interactionwith the partner of tub-1, RBG-3.

[97,98]

Osteoclast function Rab7 regulates polarization of osteoclasts and vesiculartraffic in osteoclasts, possibly through interaction withRac1 and Plekhm1.

[58,102,103]

Others

HPS and other melanogenic diseases Dysfunction of the effectors of Rab7: components of HOPscomplex.

[105–112]

ARC syndrome Genetic mutation in Rab7 down stream effector Vps33b. [113]

is similar to the constitutively active mutant Rab7-Q67L, and allthe mutants can interact with the downstream effector RILP [74].Similar properties were also studied on the Rab7-K157N mutant[73]. The results suggest that activated Rab7 and Rab7-regulatedendocytic traffic processes may be responsible for CMT2B neuro-pathies. Interestingly, another type of HSAN, HSAN-1 is due tothe mutation in the gene for SPTLC1 (serine palmitoyltrans-ferase long chain), which is involved in sphingolipid synthesis[69,75]. Since Rab7 is also involved in the transport of sphingol-ipids, CMT2B and HSAN-1 may potentially share an overlappingpathogenesis mechanism.

Rab7 regulates membrane trafficking in neuronal cells. InPC12 cells, Rab7 can associate with the NGF (nerve growthfactor) receptor TrkA (tropomyosin receptor tyrosine kinase A)at endosomes. Inhibiting Rab7 activity resulted in accumula-tion of TrkA in the endosome and potentiated NGF-stimulatedsignalling of TrkA to induce neurite outgrowth [76]. Axonaltransport contributes long-range communication in neurons andis essential for the survival and differentiation of neurons. UsingTeNT Hc (atoxic fragments of the tetanus neurotoxin) as a marker,which shares the same retrograde pathway as neurotrophins andtheir receptors, Deinhardt et al. [45] demonstrated that functionalRab7 is required for retrograde transport of the neurotrophin re-ceptor [45]. The above data suggest that dysfunction of Rab7and the disruption of Rab7-regulated membrane traffic may in-hibit neuron growth or promote apoptosis due to nutrient deficit,causing neurodegenerative diseases. Rab7 controls endosomal

trafficking of TrkA and TrkA-mediated neuritogenic signalling,and also regulates axonal retrograde transport of neurotrophin.These results may also partly explain how Rab7-regulated mem-brane traffic is responsible for CMT2B and other neurodegen-erative diseases. The reason why mutations of ubiquitouslyexpressed Rab7 have a more profound effect on peripheral neur-ons, with little effects on other tissue/organs, may be due to therequirement of more-tightly regulated membrane trafficking inneurons.

Rab7 in cancer and cell survivalAberrant endocytosis and altered lysosomal function result in de-fective growth-factor transport and unbalanced levels of surfaceproteins, such as integrins and E-cadherin, leading to tumori-genesis and cancer metastasis [77,78]. Rab GTPases, as masterregulators in membrane traffic, are proved to be involved in can-cer development [11]. Rab25 is a well-established tumorigenesis-associated Rab and is highly homologous to Rab11, and endogen-ously overexpressed in most ovarian and breast cancer samples ina constitutively active form, which is unique among Rab proteins.Cheng et al. [63] provided data indicating that overexpressionof Rab25 promotes cell transformation, inhibits apoptosis andinduces tumour progression, probably through the PI3K/AKTsignalling pathway. Rab25 may also be related to other cancersuch as OC/PPC (ovarian/primary peritoneal serous carcinoma)and prostate cancer [79].

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The results from Croizet-Berger et al. [80] showed thatthyroid hormone production was regulated by Rab5a and Rab7.cAMP stimulation elevated the expression of Rab5a andRab7 in adenomas, linking Rab7 to the formation of benignthyroid autonomous adenomas [80]. Davidson et al. [79] alsofound Rab7 is overexpressed in DMPM (diffuse peritoneal ma-lignant mesothelioma). In addition, v-Src induces activation ofRab7, which may be related to epithelial-to-mesenchymal trans-ition during tumour progression [77]. Studies by Edinger et al.[81,82] indicate that Rab7 is involved in a cell survival path-way. Upon growth-factor depletion, Rab7 down-regulates surfacenutrient transporters through endocytic degradation, preventinggrowth-factor-independent survival, but inhibition of Rab7 sus-tains surface nutrient transporters, thus promoting long-term cellsurvival, which is dependent on the AKT survival signalling path-way. Furthermore, Edinger and colleagues [81,82] demonstratedthat inhibition of Rab7 co-operated with the adenoviral E1Aprotein to promote transformation of p53−/− MEFs (mouse em-bryonic fibroblasts), thus Rab7 was proposed to act as a potentialtumour suppressor (reviewed in [7]). However, there is insuffi-cient evidence to conclude that Rab7 functions as a tumour sup-pressor. As mentioned above, Rab7 is actually overexpressed insome cancer cells or tissues, as described previously [79,80], andthe transformation effects of dominant-negative Rab7 requiredthe crucial help of the E1A protein and the absence of p53 in thestudies by Edinger and colleagues [81,82], and these studies werecarried out under nutrient starvation condition which may differslightly from the environmental conditions for tumorigenesis thatare usually rich in growth factors. Lackner et al. [83] providedanother view on the function of Rab7 in apoptosis. Inhibitingthe upstream regulator RabGGT prominently induces apoptosisof germ cells in Caenorhabditis elegans and mammalian cancercells. Lackner et al. [83] also examined the effects of knockdownof Rab5, Rab7 and components of the HOPS complex by RNAinterference in C. elegans, and found that knockdown of both Rabproteins promoted germ cells apoptosis. In addition, knockdownof the HOPS complex (comprising Vps11, Vps16, Vps18, Vps33and Vps39) also induced apoptosis, suggesting that Rab7 and theRab7-regulated pathway are involved in suppressing apoptosis[83]. In disagreement to the conclusion by Lackner et al. [83],Kinchen et al. [84] got similar results from knockdown of Rab5,Rab7 and the HOPS complex in C. elegans, but they examinedthe increase of apoptotic cells for loss of ‘cleaning’ functions bydefective phagocytosis. Taken together, the underlying mechan-ism for cancer, cell survival and apoptosis regulated by Rab7 isstill not yet understood.

Rab7 is also emerging as a regulator for the autophagic path-way, another mechanism for cell death and survival, which is re-lated to many diseases, such as cancer and heart failure [85,86].The autophagic process is initiated by engulfment of cytoplas-mic materials into a unique membrane (phagophore) to form anautophagosome; the autophagosome then undergoes maturationthrough fusion with endosomal vesicles and lysosomes to forma lysoautophagosome, in which materials are degraded to pro-vide nutrients and energy for cell survival under nutrient de-pletion. The late autophagic process is similar to late endocytic

fusion, and the mechanism for regulating autophagosome mat-uration is becoming clear, and Rab7 has been shown to be amajor factor in governing the transport and fusion events duringmaturation of autophagosome [87,88]. Furthermore, Rab7 is reg-ulated by Beclin1, a tumour suppressor able to induce autophagy,through the Beclin1–UVRAG–HOPS complex–Rab7 interactioncascade (where UVRAG is UV-irradiation resistance-associatedgene product), since the UVRAG and the HOPS complexes areeffectors for Beclin1 and Rab7 respectively [89].

Rab7 in lipid trafficking disordersSphingolipids associate with cholesterol in the plasma mem-brane to form unique lipid rafts, which play important roles inmembrane organization, cell signalling etc. [90]. Upon stimula-tion, sphingolipids and cholesterol can be internalized througheither clathrin-dependent or caveolin-mediated endocytosis intolate endosomes. In the late endosome, the sphingolipids can befurther transported to the lysosome for degradation, or the Golgiapparatus or other organelle; mis-regulation of these transportevents results in accumulation of sphingolipids in late endo-somes and causes SLSDs (sphingolipid storage diseases) [91].NPC (Niemann–Pick type C) disease is a well known SLSD,which is caused by mutations in the NPC-1 and NPC-2 genes,characterized by accumulation of sphingolipids and cholesterolin the late endosome due to a lipid traffic jam. There is evid-ence suggesting that Rab7 is linked to NPC disease [92]. Zhanget al. [93] provided data demonstrating that NPC-1 protein isassociated with the Rab7-containing late ensosome. Choudhuryet al. [94] investigated lipid trafficking in NPC cells. Their res-ults showed that the fluorescent glycosphingolipid, BODIPY®–lactosylceramide, is targeted to the Golgi in normal human skinfibroblast cells, and dominant-negative mutants of Rab7 andRab9 impaired the Golgi targeting. Furthermore, overexpressionof wild-type Rab7 or Rab9 (but not Rab11) can reduce cho-lesterol accumulation in NPC cells and restore the traffickingof BODIPY®–lactosylceramide to the Golgi, which indicates anovel potential therapeutic strategy for this disease [94]. How-ever, Lebrand et al. [95] found that overexpressing Rab7 increasedthe accumulation of cholesterol and reduced late endosomal mo-bility, which is not consistent with the study by Choudhury et al.[94]. This difference may be due to the different cell types thatwere used, but more work is required to reveal the underlyingmechanisms for the involvement of the regulation of Rab7 inNPC disease.

Intriguingly, accumulation of cholesterol affects APP (amyl-oid precursor protein) processing by inhibiting β-secretase, butenhancing γ-secretase, to produce both Aβ40 (amyloid β-peptide 40) and Aβ42, and alters presenilin localization to Rab7-positive late endosomes [96]. As discussed above, cholesterolaccumulation is also regulated by Rab7 in NPC disease cells,suggesting that Rab7 links lipid trafficking disorders to neurode-generative disease.

Rab7 is also implicated in the tub-1 pathway to regulate fatstorage. tub-1 is a transcription factor, and mutation in this generesults in adult-onset obesity, insulin resistance and progressiveneurosensory deficits [97]. Mukhopadhyay et al. [98] found that

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tub-1 interacts with the RBG-3 (RabGAP initially supposed totarget Rab3) protein, which serves as a GAP for Rab7. RNA in-terference of Rab7 can reduce fat storage in C. elegans, proposinganother role of Rab7 in lipid metabolism through interaction withRBG-3.

Although genetic defects in Rab7 have not been identified inlipid metabolism disorder, the Rab7 gene is up-regulated by acholesterol-rich diet in the liver and atherosclerotic plaques ofarteries [99], supportive for a role of Rab7 in diseases related tolipid trafficking disorders. However, the underlying mechanismsfor the regulation of Rab7 in lipid trafficking remain to be elucid-ated. In particular, little is known about the interacting partnersfor Rab7 that are involved in these regulations. Investigationsof the interaction between Rab7 and ORP1L (a member of thehuman OSBP family involved in cholesterol and sphingomyelinmetabolism) may provide one of the starting clues for studyingthese mechanisms [100].

Rab7 in osteoclast functionBone-resorbing osteoclasts are highly polarized with distinctmembrane domains: SZ (sealing zone), RB, BD (basolateral do-main) and FSD (functional secretory domain). The resorptionprocess includes: resorption of broken bone matrix in RBs, tran-scytosis of degraded materials and secretion in FSDs. Disrup-tion of bone resorption results in osteopetrosis, but excessiveresorption induces osteoporosis. The RB is a unique structurethat is similar to late endosomes/lysosomes and is character-ized by acidic environments, association with Lamp1 (lysosome-associated membrane protein 1) and Lamp2 etc. The RB is cru-cial for proper bone resorption. The function of the RB dependson vesicular trafficking regulated by Rab GTPases [101], andRab7 is one of most important Rab GTPases in regulating osteo-clast function. Rab7 is found highly expressed in bone-resorbingosteoclasts and predominantly localized to the RB. Decreasingexpression level of Rab7 disrupted the polarization of osteoclastsand impaired bone resorption in vitro [102]. The more profoundregulation mechanisms were investigated more recently. Sun et al.[58] identified Rac1 as a Rab7-interacting effector, and the Rab7–Rac1 interaction as being regulated by the formation of RBs in os-teoclasts. Furthermore, the Rab7–Rac1 interaction suggests thatRab7 regulates membrane trafficking, which is orchestrated bythe interactions between RLIP–dynein–dynactin–microtubulesand Rac1–actin filaments. In addition, a pleckstrin-homology-domain-containing protein, Plekhm1, was also characterized as apotential effector for Rab7; Plekhm1 association with Rab7 is de-pendent of the prenylation of Rab7. Loss of function of Plekhm1is responsible for osteopetrosis [103]. As Rab7 plays importantroles in osteoclasts, the modulation of Rab7 activity may be de-veloped into new therapeutic strategy for treating osteopetrosisor osteoporosis.

Rab7 in the pathogenesis of other diseasesThe melanosome is an LRO (lysosome-related organelle), andtyrosinase and TRPs (tyrosinase-related proteins) are melanomalmembrane-bound proteins that are only expressed in melano-cytes [104]. Hirosaki et al. [105] found that a dominant-negative

mutant of Rab7 impaired the vesicular transport of tyrosinase andTRPs from the Golgi to the melanosome, suggesting that Rab7is involved in the biogenesis of melanosomes. However, geneticmutations in Rab7 were not observed in diseases caused by abnor-mal melanogenesis, such as OCAs (oculocutaneous albinisms)[106]. However, the HOPS complex, which serves as an effectorand a GEF for Rab7, plays significant roles in melanogenesis, anddysfunction of the HOPS complex results in aberrant pigmenta-tion, albinisms and immuodeficiency disease, such as HPS; forexample, reduced expression of Vps11 causes less pigmentationin medaka fish [107], defects in Vps18 and Vps39 induce hypo-pigmentation in zebrafish [108,109], Vps16 is required for endo-somal trafficking and pigment-granule biogenesis in Drosophila[110], and the mouse model exhibiting the HPS phenotype resultsfrom a mutation in Vps33a [111]. Furthermore, another com-ponent of the HOPS complex, Vps41, regulates alkaline phos-phatase transport through interaction with the δ-subunit of theAP-3 adaptor, which is well characterized as being associatedwith melanogenic diseases [112]. Gissen et al. [113] reportedthat mutation in Vps33B (Vps33a isoform) causes a severe auto-somal recessive multisystem disorder, which is known as ARC(arthrogryposis-renal dysfunction-cholestasis) syndrome. In con-clusion, Rab7 is likely to be involved in melanogenic diseasesthrough interaction with its partners, such as the HOPS complex.

RAB7 IN INFECTIOUS DISEASES

In addition to diseases resulting directly from dysfunctionof Rab7 or its partners, Rab7 and its partners are import-ant factors in the pathogenesis of infectious diseases causedby micro-organisms, in which Rab7 is a key regulator in theprocess of phagosome maturation [114–118]. When microbialpathogens are engulfed by host cells (e.g. macrophages), theyreside in a membrane-bound vacuole or phagosome; the va-cuole/phagosome then fuses with late endosome to form aphagolysosome, and within the phagolysosome the pathogensare degraded. However, many microbial pathogens have evolvedelaborate mechanisms to evade degradation and therefore sur-vive within the host cells. The modulation of the function ofRab GTPases is one of the important strategies for the infec-tion and survival of microbial pathogens [14]. Rab7 is involvedin pathogenesis of infectious diseases and has been examinedin divergent microbial pathogens (Table 3), including bacteria,protozoan, fungi and viruses.

Bacteria and other microbial pathogensBacteria infect host cells through phagocytosis; Rab7, togetherwith its partners (e.g. RILP), are essential factors in regulat-ing the maturation of the phagosome into a lysophagosome,which has been well studied [119,120]. The roles of Rab7 or itspartners in bacterial infection have been studied extensively forMycobacterium tuberculosis, Mycobacterium bovis BCG,

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M. Zhang and others

Table 3 Rab7 in divergent pathogen infection and survival

Pathogen Rab7 involvement Reference

Bacteria

Mycobacterium bovis BCG Exclusion of Rab7 or RILP inhibitsMycobacterium–phagosome maturation intophagolysosomes.

[121]

Mycobacterium tuberculosis Involvement of Rab7 in bacterial phagosome maturationarrest.

[122]

Salmonella enterica Typhimurium SCV formation requires Rab7 and RILP, but Sifs maturationis dependent of abolishing Rab7–RILP interactionregulated by SifA.

[119,124–127,129]

Helicobacter pylori Rab7 and RILP regulate VacA-induced vacuolation. [132,133]

Brucella abortus Dysfunction of Rab7 or RILP impairs BCV maturation tosurvival and replication organelle.

[134]

Bacillus anthracis Rab7-T22N enhances sterne spore survival. [135]

Staphylococcus aureus Not clear. [139]

Neisseria gonorrhoeae Exclusion of Rab7 and RILP on bacterial phagosome inLamp1 and Lamp2 double-knockout cell.

[136]

Escherichia coli strain LF82 Bacteria survival acquires Rab7 function. [141]

Parachlamydia acanthamoebae Rab7 is involved in the endocytic traffic of P.acanthamoebae.

[138]

Legionella pneumophila Phagosome maturation is arrested, despite of acquisitionof Rab7.

[122]

Protozoan

Leishmania donovani Involvement of Rab7 in the biogenesis of parasitophorousvacuoles.

[115]

Trypanosoma cruzi Dominant-negative Rab7 reduces infection. [143,144]

Toxoplasma gondii Rab7 may regulate the maturation of autophagosome-likevacuole induced by T. gondii.

[145]

Others

Aspergillus fumigatus Rab7 may regulate phagocytosis and survival of conidia. [140]

Coxiella burnetii Rab7 participates in the biogenesis of C. burnetii-inducedautophagosome-like vacuole.

[137]

Virus

Adenovirus serotype 7 (Ad7) Virus co-localizes with Rab7. [155]

Influenza virus Dominant-negative Rab7 inhibits infection. [156]

SFV Expression of Rab7-T22N results in accumulation of SFVsin early endosomes and reduces virus entry.

[157]

SFV fus-1 Infection was inhibited by Rab7-T22N. [159]

VSV VSV entry was reduced by Rab7-T22N. [158]

HIV-1 Overexpression of Rab7 results in an almost completeblockade of HIV-1 gene expression in trophoblasts.

[160]

DENV DENV matures in late endosomal compartments byacquisition of Rab7 and loss of Rab5.

[162]

Pichinde virus Knockdown of Rab7 results in 80% reduction of productionof viral proteins.

[164]

Recombinant adeno-associatedvirus type-2 (rAAV2)

Overexpression of Rab7 decreases rAAV2 transduction. [165]

Ebola virus Expression of Rab7-T22N inhibits entry of Ebola viruspseudoparticles.

[166]

Group C adenovirus Rab7 may regulate viral life cycle throughRILP–ORP1L–RIDα interaction.

[172]

VEEV Rab7-T22N significantly inhibits entry of virus; VEEVinfection requires Rab7 in mosquito cells.

[158,170]

White-spot syndrome virus (WSSV)and yellow head virus (YHV) inPenaeus monodo

Suppression of Rab7 inhibits viral infection. [168,169]

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Salmonella enterica Typhimurium, Helicobacter pylori and oth-ers (Table 3).

M. tuberculosis is the most virulent pathogen in human his-tory, causing over 1 billion people to suffer from tuberculosis.Via et al. [121] first established the phagosome-arrest model forpathogen survival in host cells during M. bovis BCG infection,In this model, two Rab proteins, Rab5 and Rab7, play key rolesin controlling Mycobacterium phagosome maturation. The form-ation of Mycobacterium-containing phagosomes requires Rab5;but selective exclusion of Rab7 blocks phagosome fusion withlate endosomes, and results in Mycobacterium-containing pha-gosome arrest in early stage, and therefore Mycobacterium canescape degradation and survive in host cells. The selective ac-cumulation of Rab5 and exclusion of Rab7 defines the check-point in the mycobacterial phagosome maturation process. In-terestingly, Clemens et al. [122] found that M. tuberculosis andLegionella pneumophila phagosomes still exhibited arrested mat-uration, despite acquisition of Rab7, and phagosomes contain-ing live M. tuberculosis recruit even more active Rab7 in HeLacells, and the authors [122] proposed that this discrepancy waslikely due to using different cell types (macrophages and epi-thelial cells), different bacteria species (M. bovis BCG andM. tuberculosis) and different detection technologies. Never-theless, subsequent investigations may provide a more mechan-istic explanation for phagosome maturation arrest, even with theacquisition of Rab7 to Mycobacterium-containing phagosomes.The Rab7 downstream effector RILP is also required for phago-some maturation; the results from Sun et al. [120] indicated thatM. bovis BCG inhibited RILP recruitment, despite Rab7 acquis-ition by the phagosome, therefore inhibiting phagosome matura-tion, in addition, Rab7 (GDP-bound form) predominates in cellsinfected with live M. bovis BCG, and the M. bovis BCG culturesupernatant contains a factor that catalyses the GTP/GDP switchon recombinant Rab7 molecules. Previous studies [122] indicatedthat the modulation the conversion of Rab5 into Rab7 is a crucialmechanism for Mycobacterium-containing phagosome matura-tion arrest. A study by Roberts et al. [118] revealed that Rab22a,an early endosomal Rab protein, is also critical in regulating Rab7conversion on phagosomes during M. tuberculosis infection, andRab22a knockdown in macrophages via siRNA (small interferingRNA) enhanced the maturation of phagosomes with live Myco-bacteria by increasing the association of Rab7 with phagosomes.M. tuberculosis may actively recruit and maintain Rab22a onits phagosome, thus inhibiting Rab7 acquisition and blockingphagolysosomal biogenesis [118]. Philips et al. [123] reportedthat ESCRT (endosomal sorting complex required for transport)factors (VPS28, TGS101 and VPS4 were examined in [123]),as well as Rab7, restrict Mycobacterium smegmatis growthin Drosophila and mammalian cells. Because RILP interactswith the ESCRT II complex [53,54], Rab7 may regulateMycobacteria-containing phagosome maturation through regu-lating ESCRT machineries in Mycobacteria infection. Taken to-gether, Rab7 is involved in Mycobacteria infection, which isregulated by other factors.

S. enterica Typhimurium is a facultative pathogen, which in-vades various cell types, including epithelial cells and macro-

phages. Infection experiments in vitro revealed that Salmonellaresides within SCVs (Salmonella-containing vacuoles) after en-tering into host cell. In SVCs, bacteria induce expression of SPI-2(Salmonella pathogenicity island 2)-encoded TTSS (type III se-cretion system) effector SifA. SifA regulates SCV maturationinto Sifs (Salmonella-induced filaments), allowing for maximalspace for bacteria replication; and Sifs will not fuse with lyso-somes, permitting bacteria survival and replication. The rolesof Rab7 in SCVs have been investigated. Merésse et al. [124]showed that Rab7 is associated with SCV, and Rab7 may controlthe biogenesis of SCVs by recruiting lgps (lysosomal glycopro-teins) to SCVs, suggesting that SCV maturation requires fusionwith late endosomal membranes regulated by Rab7. Studies byBrumell et al. [125] indicated that Rab7 was also present in Sifs,and expression of the dominant-negative mutant Rab7-N125I in-hibited Sif formation. In addition, overexpression of Rab7-N125Icaused a loss of SCV integrity and increased Salmonella replica-tion in the cytosol [126]. Drecktrah et al. [127] confirmed that theacquisition of endosome/lysosome content by SCVs is Rab7 de-pendent using a high-resolution live-cell-imaging approach. An-other study by Harrison et al. [119] revealed that the maturationof SCVs and Sifs is regulated by Rab7 and its effector RILP. Theinitial centripetal displacement of the SCV is due to recruitmentof RILP by Rab7, which may govern the centripetal move-ment of the SCVs through interaction with dynein–dynactin com-plex. When Sifs are induced, RILP is depleted, despite the pres-ence of Rab7. As a result, Sifs extend towards the periphery. Inthe process of Sif formation, the bacterial factor SifA is criticalfor disengaging of RILP from Rab7, which may serve as an inter-action partner for Rab7. In summary, although many Rab proteinsmay associate with SCVs or Salmonella phagosome [128], Rab7is probably the most important Rab protein in SCV biogenesis, inthat SCV maturation requires Rab7–RILP to regulate SCV fusionwith late endosomal membrane to gain some late endosomal com-ponents, such as Lamp proteins, cathepsin D and LBPA (lyso-bisphosphatic acid), determining SCV and Sifs as special struc-tures different from Mycobacterium–phagosome. Nevertheless,a previous study by Hashim et al. [129] demonstrated that liveLSPs (Salmonella-containing phagosomes) retain a significantamount of Rab5, but selectively deplete Rab7 and Rab9, with aproperty similar to Mycobacterium–phagosome, suggesting thatdifferent conditions in vitro, such as different cell types, bacteriastrains etc., may give rise to different outcomes.

H. pylori is another representative micro-organism that pos-sesses a survival strategy through modulating Rab7 function to es-cape degradation in host cells. In host cells, H. pylori releases thetoxin VacA. VacA induces vacuolation, generating enlarged andperi-nuclear-distributed Helicobacter-containing vacuoles. Thisvacuole, containing the late endosomal markers Rab7, Lamp1 andCD63, but not Rab5, mannose-6-phosphate receptor, transferrinreceptor and cathepsin D [130], has been described as a post-endosomal hybrid compartment, with both late endosomal andlysosomal features [131]. Since the VacA-induced vacuoles lackthe ability of degradation, bacteria can survive in this specializedstructure. Rab7 was shown to be essential for the biogenesis ofthe VacA-induced vacuoles [132]. The active Rab7-Q67L mutant

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M. Zhang and others

enhances VacA-induced vacuolation, whereas Rab7-T22N orRab7-N125I effectively inhibits vacuolation. Rab5 and Rab9have less effect. In addition to the engagement of Rab7 in VacA-induced vacuolation, the Rab7 effector RILP is also associatedwith the VacA-induced vacuoles. RILP is thought to regulate largevacuole formation and cellular distribution of the VacA-inducedvacuoles. Furthermore, the interaction between Rab7 and RILPis important for vacuolation, as the expression of mutant formsof RILP or Rab7 that failed to bind each other impaired the form-ation of this unique bacteria-containing vacuole [133]. Thesedata suggest that VacA prevents the maturation of the Helicobac-ter-containing vacuole into a bactericidal structure by retentionof Rab7 and RILP. How VacA-induced vacuole maintains itsunique characteristics for bacteria survival and whether VacA in-teracts with Rab7 or RILP (or other Rab7 effectors) remain to beanswered.

The roles of Rab7 were also examined in phagocytosis ofother microbial pathogens (Table 3). Brucella abortus invadeshost cells and resides within BCVs (Brucella-containing vacu-oles). BCVs fuse with the ER (endoplasmic reticulum)-derivedmembrane structure to generate a replicative organelle. It hasbeen observed that both Rab7 and RILP were recruited to theBCVs during BCV maturation. Overexpression of the dominant-negative Rab7-T22N or RILP impaired biogenesis of the ER-derived organelle and replication of bacteria [134], suggestingthat BCV maturation requires interactions with functional lateendosomal/lysosomal compartments. In phagocytosis of Bacil-lus anthracis spores, expression of the dominant-negative Rab7-T22N, which blocked lysosomal fusion, enhanced sterne sporesurvival [135]. Exclusion of Rab7 and RILP on bacterial pha-gosomes in a Lamp1/Lamp2 double-knockout cell infected byNeisseria gonorrhoeae indicated that Rab7 is involved in the mat-uration arrest of N. gonorrhoeae-containing phagosomes [136].Rab7 and Rab7-Q67L localized to Coxiella burnetii-inducedautophagosome-like vacuoles, suggesting that Rab7 participatesin the biogenesis of this pathogen-containing vacuole [137]. Rab7may regulate Parachlamydia acanthamoebae trafficking alongthe endocytic pathway [138], and is probably engaged in thesurvival strategies by Staphylococcus aureus [139]. Rab7 mayalso participate in regulating phagocytosis and the intracellu-lar fate of conidia of the fungal pathogen Aspergillus fumigatus[140]. Interestingly, some bacteria, such as the Crohn’s disease-associated adherent–invasive Escherichia coli strain LF82, do notescape from the endocytic pathway, but undergo a normal inter-action with the host endomembrane organelles, acquiring Rab7function, and replicate within acidic and cathepsin D-positive va-cuolar phagolysosomes [141]. The mechanisms for the bacteriaescaping degradation are not clear.

In protozoa infection, wild-type Leishmania donovani pro-mastigotes inhibit phagosome maturation due to impaired re-cruitment of Rab7, prolonging bacterial survival in the mur-ine macrophage cell line J774 [115]. Rab7 was found only inthe PVs (parasitophorous vacuoles) of mature BMDCs (bone-marrow-derived cells), and it was absent in immature BMDCs,suggesting an arrest of their PV biogenesis at the stage of thelate endosome [142]. Trypanosoma cruzi invades cells through

the endocytic pathway where expression of dominant-negativeRab7 reduces infection, with the same effects found for Rab5and dynamin [143]. In addition, T. cruzi down-regulates Rab7in T. cruzi-infected cardiomyocytes [144]. Rab7 may also regu-late the maturation of autophagosome-like vacuoles induced byToxoplasma gondii; experiments inhibiting PI3K, Rab7, vacuolarATPase and lysosomal enzymes revealed the vacuole/lysosomefusion event mediates antimicrobial activity which is induced byCD40 [145].

In summary, Rab7 plays a central role in regulating phago-some maturation when cells are infected by microbial patho-gens. Microbial pathogens possess survival strategies governedby Rab7, sometimes by employing Rab7 function (e.g. Salmon-ella) and sometimes by excluding Rab7 function (e.g. Mycobac-terium). As shown in Figure 3, microbial pathogens infect cellsthrough phagocytosis and survive in host cells with a similarphagosome-arrest strategy by manipulating the function of Rabproteins. Pathogens enter host cells and reside in nascent pha-gosomes with reduced acidification. This pathogen-containingphagosome requires Rab5 GTPase to fuse with early endosometo form early phagosome; the early phagosome then fuses withlate endosome to form a phagosome, acquiring some late endo-somal components, but usually fails to recruit Rab7 GTPase orits partners, preventing phagosome maturation into phagolyso-some and allowing pathogen survival in the arrested phagosome.Some pathogen-containing phagosomes are also arrested by par-tial acquisition of late endosomal components, including Rab7,and form a late endosome/phagosome hybrid, which also cannotmature into a bactericidal phagolysosome. The important roles ofRab7 in diseases caused by micro-organisms suggest that modu-lation of Rab7 function may be a potential treatment strategy.

VirusViruses infect cells and take over cellular machineries for replica-tion, viral particle assembly and release. It is well established thatmembrane trafficking machineries play key roles in the viral lifecycle [146–148]. Most enveloped viruses enter cells via clathrin-mediated endocytosis, and are trafficked through the early endo-dome to the late endosome/lysosome, then release viral materialsinto cytosol, via an unknown mechanism, due to lysis/leakageof endosomal compartments. It has been revealed that buddingand release of some viruses, such as HIV and HBV (hepatitis Bvirus), requires MVB machineries, such as ESCRT complexes[149–152].

Small GTPases participate in regulating viral life cycle[153,154]. The effects of Rab7 on viral infection were examinedfor some viruses (Table 3). Miyazawa et al. [155] reported thatinternalized Ad7 (adenovirus serotype 7) was co-localized withRab7 and other late endosomal/lysosomal markers, suggestingthat the late endosomal trafficking pathway is involved in viralinfection [155]. Sieczkarski and Whittaker [156] found thatdominant-negative Rab7 inhibited infection of influenza virus,without effects on the infection of SFV (Semliki Forest virus) andVSV, which were inhibited by dominant-negative Rab5. How-ever, the findings by Vonderheit and Helenius [157] indicatedthat the internalized SFV is finally located to the Rab7 membrane

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Figure 3 A common survival strategy for pathogens through phagosome maturation arrest regulated by Rab7Non-pathogen induced-vacuoles (nascent phagosome) can fuse with the early endosome to form early phagosomesby acquisition of Rab5; early phagosomes then fuse with late endosomes and lysosomes to form phagosomes andphagolysosomes by acquisition of Rab7 and loss of Rab5. Pathogen-induced vacuoles acquire Rab5 and fuse with theearly endosomes to form early phagosomes; the pathogen-containing early phagosome is prevented from fusion with lateendosomes and lysosomes by pathogen-mediated exclusion of Rab7, allowing pathogen survival in the arrested phago-some. Some pathogen-containing phagosomes are also arrested by partial acquisition of late endosomal components,including Rab7 (indicated by the broken line with an arrow), and form late endosome–phagosome hybrids. See the text forfurther details.

domain, excluding Rab5, Rab4, EEA1 and Arf1, and overexpress-ing dominant-negative Rab7 resulted in accumulation of SFV inthe early endosome [157]. Similarly, Kolokoltsov et al. [158]found that SFV and VSV entry was reduced by 20% when Rab7-T22N was expressed in cells. Quirin et al. [159] found SFV in-fection was not inhibited by the corresponding Rab7-T22N con-struct, but an SFV mutant stain (SFV fus-1) infection was in-hibited by Rab7-T22N. Feng et al. [21] found that the VSV Gprotein was accumulated specifically in early endosomes in babyhamster kidney cells expressing the Rab7-N125I mutant. Vidri-caire and Tremblay [160] investigated the roles of Rab7 in HIV-1infection in polarized human placental cells, and demonstratedthat overexpression of both the dominant-negative and dominant-active Rab7 resulted in an almost complete blockade of HIV-1gene expression (up to 88% inhibition in viral expression was ob-served). When studying the trafficking of HIV-1 genomic RNA,Lévesque et al. [161] found that overexpression of RILP had littleeffect on the synthesis of the polyprotein precursor Pr55Gag, butnegatively influenced virus production and infectivity. Recently,van der Schaar et al. [162] used live-cell imaging and single-virustracking to investigate the cell entry, endocytic trafficking and fu-sion behaviour of DENV (Dengue virus), and demonstrated thatDENV matured in late endosomal compartments by acquisitionof Rab7 and loss of Rab5, similar to the phagosome maturation asdescribed above. On the other hand, Krishnan et al. [163] found

that depletion of Rab7 or Rab7 mutant overexpression did notimpair DENV and WNV (West Nile virus) infection of HeLacells. In mammalian cells, data from Kolokoltsov et al. [158]demonstrated that VEEV (Venezuelan equine encephalitis virus)entry was reduced by Rab7-T22N by 80–90%. Similar findingsby Vela et al. [164] revealed that Pichinde virus enters cellsthrough Rab5–early endosomes, and then uncoats and fuses withRab7–late endosomes, and knockdown of Rab7 resulted in 80%reduction of viral protein production of Pichinde virus. Ding et al.[165] showed that overexpression of Rab7 significantly decreasedrAAV2 (recombinant adeno-associated virus type-2) transduc-tion. Meertens et al. [166] found that expression of Rab7-T22Ninhibited entry of Ebola virus pseudoparticles. Smith et al. [167]observed that HPV31 (human papillomavirus type 31) capsids in-creased residence in the caveosome in mutant-Rab7-transfectedcells, but no infection inhibition was detected. The results suggestthat, although some discrepancies exist between different studies,Rab7 and Rab7-associated endosomes are intimately involved inentry of some viruses.

Evidence for the involvement of Rab7 in viral infectionwere also studied in a non-mammalian system. Suppression ofPmRab7 (a Rab7 homologue in Penaeus monodon) inhibitsthe infection of WSSV (white-spot syndrome virus) throughinteraction with viral protein VP28 [168], and similar inhibi-tion was also found for YHV (yellow-head virus) in P. monodon

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M. Zhang and others

[169]. VEEV infection of mosquito cells requires the mosquitohomologue of Rab7 [170]. The requirement for Rab7-mediatedmembrane trafficking in viral infection of a non-mammalian sys-tem revealed an evolutionarily conserved pathway.

Rab7 may also be engaged in host-cell defence against viruses;for example, the HIV-1 protein Nef targets MHC-I and CD4 to aRab7-positive compartment for degradation [171], which may bethe mechanism by which the virus escapes attack from the host’simmune system. Taken together, Rab7-mediated endosomal traf-ficking plays important roles in viral infection; however, the rolesof Rab7 in the transport, assembly of newly synthesized viral pro-tein and release of a new viral particle remain unclear. A recentfinding by Shah et al. [172] characterized the group C adenov-irus protein RIDα (receptor internalization and degradation α),which interacts with RILP and ORP1L, both of which are effect-ors of Rab7. The results of this study [172] also indicated thatRIDα mimics the function of Rab7 to recruit RILP to endosomesto facilitate down-regulation of the surface receptor. These dataprovide another virus–host interaction model. Further studies onRIDα–ORP1L–RILP–Rab7 orchestration may reveal additionalmechanisms for Rab7 to regulate viral life cycle.

SUMMARY

In summary, Rab7 is engaged in divergent disease pathogenesis,physiological disorders and infectious diseases. The fundamentalmechanisms depend on the crucial role of Rab7 in regulating en-docytic membrane trafficking, therefore governing the biogenesisof endocytic compartments (late endosome, lysosome, phago-some, autophagosome and other functionally similar organelles)and linking the trafficking events to cell signalling pathways thatinfluence multiple cellular events. Nevertheless, much work re-mains to further the understanding of pathogenic mechanismsfor regulation of diseases by Rab7, such as how the function ofRab7 is regulated by its different effectors. The significance ofthe interactions between Rab7 and its effectors in regulating dis-ease pathogenesis has not been elucidated in detail. Furthermore,since most investigations are carried out in vitro using culturedcells, the in vivo system using animal models will advance addi-tional knowledge about the underlying mechanisms of Rab7 (orits partners) in endosomal trafficking and its involvement in thedevelopment of various diseases.

FUNDING

This work was supported by the start-up funds for new investigatorsfrom Xiamen University, People’s Republic of China.

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