review article role of inositol phosphosphingolipid...

Review ArticleRole of Inositol Phosphosphingolipid Phospholipase C1,the Yeast Homolog of Neutral Sphingomyelinases in DNADamage Response and Diseases

Kaushlendra Tripathi

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue,Mobile, AL 36604, USA

Correspondence should be addressed to Kaushlendra Tripathi; [email protected]

Received 26 June 2015; Revised 25 July 2015; Accepted 29 July 2015

Academic Editor: Alessandro Prinetti

Copyright © 2015 Kaushlendra Tripathi. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Sphingolipids play a very crucial role in many diseases and are well-known as signaling mediators in many pathways. Sphingolipidsare produced during the de novo process in the ER (endoplasmic reticulum) from the nonsphingolipid precursor and compriseboth structural and bioactive lipids. Ceramide is the central core of the sphingolipid pathway, and its production has been observedfollowing various treatments that can induce several different cellular effects including growth arrest, DNA damage, apoptosis,differentiation, and senescence. Ceramides are generally produced through the sphingomyelin hydrolysis and catalyzed by theenzyme sphingomyelinase (SMase) in mammals. Presently, there are many known SMases and they are categorized into threegroups acid SMases (aSMases), alkaline SMases (alk-SMASES), and neutral SMases (nSMases).The yeast homolog of mammaliansneutral SMases is inositol phosphosphingolipid phospholipase C. Yeasts generally have inositol phosphosphingolipids instead ofsphingomyelin, which may act as a homolog of mammalian sphingomyelin. In this review, we shall explain the structure andfunction of inositol phosphosphingolipid phospholipase C1, its localization inside the cells, mechanisms, and its roles in various cellresponses during replication stresses and diseases.This review will also give a new basis for our understanding for the mechanismsand nature of the inositol phosphosphingolipid phospholipase C1/nSMase.

1. Introduction

In the eukaryotic cell, sphingolipids make up an imperativeset of regulatory molecules and they are involved in a broadarray of cellular activities such as cell growth, inflammation,checkpoint, angiogenesis, and stress stimuli [1–3]. Baker’syeast Saccharomyces cerevisiae has been used by variousresearchers as a model for studying the sphingolipid biosyn-thesis because of its ease in sphingolipid metabolism ascompared to mammalian systems [3, 4]. The set of bioactivesphingolipids includes ceramide, sphingosine, sphingosine-1-phosphate, and ceramide-1-phosphate. The mammalianneutral sphingomyelinase (nSMase 2) ortholog in yeast isinositol phosphosphingolipid phospholipase C1 (ISC1). Bac-terial nSMase sequence analysis facilitated in the revealingof yeast nSMase inositol phosphosphingolipid phospholi-pase C1 and nSMases of mammals. It is encoded by the

inositol phosphosphingolipid phospholipase C gene in Sac-charomyces cerevisiae and Cryptococcus neoformans [5, 6].In fission yeast Schizosaccharomyces pombe, it is encodedby the gene CSS1 known as Can’t Stop Synthesizing cellwall and ISCL gene in Leishmania major. ISC1/nSMase 2are well-known to catalyze the degradation of complexphosphosphingolipids into phytoceramide/dihydroceramidein Saccharomyces cerevisiae and ceramide/dihydroceramidein mammals [7]. Ceramides are well studied bioactive lipidsand known to play a crucial role in various cell functions suchas senescence, growth, and apoptosis and at the time of stress[8]. Yeast cells lacking inositol phosphosphingolipid phos-pholipase C exhibit a slower growth rate than its wild typestrains [9]. These cells also show higher sensitivity to highsalt concentration (NaCl), hydrogen peroxide and and lead toG2/Marrest after hydroxyurea drug treatment [5, 10]. Variousgroups have also shown that inositol phosphosphingolipid

Hindawi Publishing CorporationJournal of LipidsVolume 2015, Article ID 161392, 6 pageshttp://dx.doi.org/10.1155/2015/161392

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phospholipase C protein plays an important role not only inchronological lifespan but also in oxidative stress resistance[10, 11]. Inositol phosphosphingolipid phospholipase C alsoregulates the cellular redox homeostasis via inflection of ironlevels. Loss of inositol phosphosphingolipid phospholipaseC gene decreased cells hypersensitive to hydrogen peroxide,hydroxyurea, and methyl methanesulfonate compared withthe wild type cells. A genome-wide transcriptome analysisrevealed that the deletion of inositol phosphosphingolipidphospholipase C leads to an increase of messenger RNAlevels of nearly about seventy-two genes and a decline ofnearly about 142 genes. This clearly indicates that inositolphosphosphingolipid phospholipase C plays a crucial role inthe cells.

In pathogenic fungi, Cryptococcus neoformans inositolphosphosphingolipid phospholipase C is also known tometabolize the fungal inositol sphingolipids [12]. It is alsowell-known that inositol phosphosphingolipid phospholi-pase C enhances Cryptococcus neoformans endurance inmacrophages that is vital for controlling the spreading of thisinfectious pathogen into the brain [13]. The inositol phos-phosphingolipid phospholipase C deleted (isc1Δ) mutant ofCryptococcus neoformans strain shows another characteristicfeature of hyperencapsulation. Inositol phosphosphingolipidphospholipase C, fission yeast homolog Css1p hydrolyzedIPC to the same level as inositol phosphosphingolipid phos-pholipase C in baker’s yeast. Furthermore, the genome-wide screen also revealed that inositol phosphosphingolipidphospholipase C deleted (isc1Δ) mutants were sensitive tomethyl methanesulfonate (MMS), a DNA alkylating agentand the DNA replication blocking drug hydroxyurea [14]. Inthe later section of this review, we will discuss more about theeffects of these drugs.

2. Sphingolipids in Yeast

Yesteryear, the baker’s yeast Saccharomyces cerevisiae hasemerged as a great tool in the study of sphingolipid func-tion and its metabolism. Firstly, in yeast most of the keyenzymes involved in the metabolism of bioactive sphin-golipids were identified. Stress stimuli such as heat stressplay a crucial role in the regulation of acute production ofbioactive sphingolipids in yeast [1, 15]. Sphingolipids havebeen involved in mediating several important responses intothe cell such as cell cycle arrest and regulation of proteintranslation. One of the important steps that appears to actin sphingolipid mediated signal pathway is the activationof the inositol phosphosphingolipid phospholipase C. Inos-itol phosphosphingolipid phospholipase C has substantialsimilarity to mammalian SMases that have direct effect onanimal sphingolipid signaling pathway [5]. In mammals, atpresent there are five different kinds of nSMases known,such as nSMase 1, nSMase 2, nSMase 3, and mitochondrialassociated nSMase (MA-nSMase), which are decoded by fivegenes SMPD2 (sphingomyelin phosphodiesterase 2), SMPD3,SMPD4, and SMPD5, respectively.

The sphingolipid biosynthesis starts with the conden-sation process of fatty acyl-CoA and serine through the

enzyme complex serine palmitoyltransferase (SPT) (Figure 1)[16]. Serine palmitoyltransferase complex enzyme consists oftwo major subunits which are coded by two different geneslong chain base 1 (LCB1/YMR296C) and long chain base 2(LCB2/YDR062W) and a third small subunit, encoded bythe gene TSC3 (temperature-sensitive suppressor of csg2Δ).In mammals, serine palmitoyltransferase complex enzymeis encoded by three different genes SPTLC1 (mutation in itlinked to sensory neuropathy, type 1), SPTLC2, and SPTLC3.It requires pyridoxal-5-phosphate as a cofactor and enduresfunctional and sequence homology to 𝛼-oxoamine synthasesgroup of enzymes [17, 18]. In vivo and in vitro studiesunambiguously suggest that both serine palmitoyltransferase1 (Lcb1p) and serine palmitoyltransferase 2 (Lcb2p) arerequired for serine palmitoyltransferase complex activity.Though, point mutants in LCB2 amplified serine palmitoyl-transferase complex activity in the absence of TSC3. Thisindicates that Tsc3p mediates serine palmitoyltransferaseactivation probably through interaction with the subunitof Lcb2p [19, 20]. The serine palmitoyltransferase complexproduces 3-ketodihydrosphingosine that is quickly convertedinto dihydrosphingosine in an NADPH dependent way bythe enzyme 3-ketodihydrosphingosine reductase decoded bythe gene TSC10/YBR265w (temperature-sensitive suppressorof csg2Δ) [21]. In mouse and human, it is encoded by thegenes known as the human FVT-1 (hFVT-1) andmouse FVT-1 (mFVT-1) [22]. These steps clearly suggest that yeast andmammals share a lot of similarities at the initial steps ofsphingolipid metabolism pathway [23].

Differences in the sphingolipid metabolism pathwaysbetween yeast andmammals begin to arise after the above twosimilar steps. Dihydrosphingosine is generally hydroxylatedby the enzyme suppressor of rsv161/syringomycin responseprotein 2 (Sur2p/Syr2p), in S. cerevisiae to generate phytosph-ingosine. Ceramide synthases, Lag1 and Lac1, later acylatephytosphingosine while in mammalian cells dihydrosphin-gosine is straightforwardly acylated into dihydroceramide bythe action of enzymes Lac1p and Lag1p. Longevity assurancegene cognate 1 (LAC1) and longevity assurance gene 1 (LAG1)encode the protein Lac1p and Lag1p, respectively. The yeastenzymes Lac1p and Lag1p have high homology to mam-malian six Lass’s (longevity assurance)/CerS1-6 [23]. CerS1-6 are known as (dihydro)ceramide synthases in mammalsand translated by six different genes (CERS1-6/LASS1-6) thatmainly localized into the ER. In mammals, dihydroceramidedesaturase enzyme converts dihydroceramide into ceramide.In yeast, the following complex sphingolipids are synthesizedfrom phytoceramide such as mannosylinositol phospho-rylceramide (MIPC), inositol phosphorylceramide (IPC),and mannosyldiinositol phosphorylceramide (M(IP)

2C). In

case of mammals many complex sphingolipids, such assphingomyelin, galactosylceramide, and glucosylceramide,are synthesized. Sphingosine is generated by the removal ofan acetyl group from the ceramide through the action ofmany ceramidases. Ceramide phosphate is produced by thephosphorylation of ceramide via the sphingolipid pathwayenzyme ceramide kinase which transfers phosphate group toceramide [7, 23].

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Palmitoyl CoA and L-serine

3-Ketodihydrosphingosine

Dihydrosphingosine

PhytosphingosineDihydroceramide

GalactoceramideSphingomyelin

CeramideSMase

Glucoceramide

Ceramide phosphate

Sphingosine

Sphingosine-1-phosphate

Phytoceramide

IPC

MIPC

ISC1

M(IP)2C

SPT

NADPH 3-Ketodihydrosphingosine reductase

SUR2

Lag1 and Lac1

AUR1

CSG1, CSG2

IPT1

DES

SMS

Ceramidase

Sphingosine kinase

Figure 1: The flow diagram represents the sphingolipid metabolism pathways both in mammals and in yeast. The common steps in both theorganisms are shown in yellow boxes. The yeast sphingolipid metabolism pathway steps are shown in red boxes while mammals pathway areshown in green boxes; the positions of sphingomyelinase (SMase) and inositol phosphosphingolipid phospholipase C1 (ISC1) are shown ingreen and red letters, respectively.

3. Structure and Function ofInositol PhosphosphingolipidPhospholipase C Proteins

Sawai et al. reported that geneYER019w decodes the IPS-PLCand possesses homology to bacterial neutral sphingomyeli-nase [24]. They named this gene as inositol phosphosphin-golipid phospholipase C1 for IPS-PLC, while in mammalsit has two homologs nSMase 1 and nSMase 2. N-SMaseactivity was first observed in patients with Niemann-Pickdisease, who exhibit deficiencies in aSMase [25]. They alsodetected that upregulation of inositol phosphosphingolipidphospholipase C1 gene in S. cerevisiae dramatically increasedN-SMase as well activities of all IPSs including (M(IP)

2C),

IPC, and MIPC and has a size of ∼55 kDa [24]. Greenfluorescent protein tagging analysis indicates that inositolphosphosphingolipid phospholipase C1 proteinmainly local-ized to endoplasmic reticulum and mitochondria. Moreover,various groups have also shown that deletion of the inositolphosphosphingolipid phospholipase C gene causes absolutefailure of phospholipase C (PLC) activity for all IPSs. Thisclearly suggests that inositol phosphosphingolipid phospho-lipase C is possibly the only known gene encoding IPS-PLCactivities. The yeast N-SMases inositol phosphosphingolipidphospholipase C and CSS1 have nearly about 35% similarityto each other. Mammalian SMases nSMase 1 and nSMase 2show about 28% homology to the yeast inositol phosphos-phingolipid phospholipase C. Inositol phosphosphingolipid

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phospholipase C protein has two domains: the N-terminalcatalytic active domainwhich presents outside themembraneand interact with the lipid substrates [24].The second domainis known as C-terminal domain and shows interaction withthe anionic phospholipids phosphatidylglycerol (PG), cardi-olipin (CL), and phosphatidylserine (PS). Inositol phospho-sphingolipid phospholipase C protein is generally activatedby the cardiolipin (CL), phosphatidylglycerol (PG), andphosphatidylserine (PS). Mutation in three known extremelyconserved amino acids, for example, E100, D233, and H334,of the catalytic domain of inositol phosphosphingolipidphospholipase C protein completely decreases the inositolphosphosphingolipid phospholipase C activity. The proteinblast analysis of inositol phosphosphingolipid phospholipaseC1 with bacterial sphingomyelinase indicates that residueE100 is likely to function in metal ion binding, the D234residue works in an interaction with the phosphate group ofsphingomyelin, and H344 is responsible for catalytic activity[26]. Mutation at site of D163 and K168 to alanine in the P-loop-like domain of inositol phosphosphingolipid phospho-lipase C1 completely abrogated inositol phosphosphingolipidphospholipase C protein activity, suggesting an essentialrole in catalysis for both amino acids. The amino acidsD163 and K168 are conserved among all sphingomyelinasesfrom bacteria to mammals [26]. In Cryptococcus neoformansIPC-PLC activity completely lost in case D114A and K119Amutations suggesting that these two amino acids are verycrucial for the catalytic activity of Cryptococcus neoformansinositol phosphosphingolipid phospholipase C1 [6].

4. Role of InositolPhosphosphingolipid Phospholipase Cin DNA Damage Checkpoint

Many groups have already shown the relationship betweenceramides and DNA damage response after the ionizingradiation [27]. The cross talk between ceramides and DNAdamage is also well elucidated [28]. We and others haveshown that inositol phosphosphingolipid phospholipase C1plays a crucial part in determining the cellularmorphology ofthe cells at the time of replication stress in yeast. Furthermore,we and others have also observed that inositol phosphos-phingolipid phospholipase C is an important controller ofcellular morphogenesis under various kinds of genotoxicand environmental stress [29]. During hydroxyurea inducedreplication stress cells lacking inositol phosphosphingolipidphospholipase C lead to morphological changes and aberra-tion in actin depolymerization. It is well-known that hydrox-yurea activates inositol phosphosphingolipid phospholipaseC and increases the ceramides. The mediators proteins ofreplication checkpoint, topoisomerase I interacting factor(Tof1) and chromosome segregation in meiosis 3 (Csm3),do not play a foremost role in transduction of the signalsgenerated in inositol phosphosphingolipid phospholipaseC1 depleted cells during hydroxyurea treatment. However,inositol phosphosphingolipid phospholipase C functions inparallel with these checkpoint mediators and control the cellgrowth and morphology in normal cells. Rad9 the mediator

of DNA damage induced checkpoint plays a crucial role tocontrol signals generated at the time of replication stress ininositol phosphosphingolipid phospholipase C knockdowncells, leading to the cell morphological defects. It is reportedby many groups that Rad53 controls cellular morphology inyeast cells. The DNA damage induced checkpoint effectorprotein Rad53 kinase, activated by Rad9 at the time ofDNA damage, and also controls hydroxyurea dependentmorphological abnormality in inositol phosphosphingolipidphospholipase C depleted cells. This clearly signifies thatDNA damage induced checkpoint pathway molecules areactive under these stress conditions and play an importantrole [30]. Interestingly, mitosis inhibitor protein kinase SWE1and cyclin-dependent kinase 1 (Cdk1) were found to controlnot only the cell cycle of yeast cells but also the morpholog-ical defects of inositol phosphosphingolipid phospholipaseC depleted cells [31]. Lastly, it has been also shown thatrole of inositol phosphosphingolipid phospholipase C in themaintenance of cellular morphology was not restricted toonly replication stress. This sphingolipid pathway gene wasalso well-known to regulate the shape of the cell and itsmorphology under other stress conditions, such as aftertreatment of galactose sugar and butanol alcohol [30, 32, 33].

5. Role of Inositol PhosphosphingolipidPhospholipase C in Pathogenesis

Inositol phosphosphingolipid phospholipase C one side playsa crucial role during the checkpoint while other ways havealso shown that sphingolipid metabolism is closely linkedto the virulence of pathogenesis of Cryptococcus neoformans(Cn). The Cryptococcus neoformans is a serious menace toimmunocompromised, especially for the person sufferingfrom the disease HIV and immunocompetent individualsalso [12]. As we discussed earlier Inositol phosphosphin-golipid phospholipase C has been characterized in S. cere-visiae [24] Cryptococcus [6] and Leishmania [34], suggestingthat this sphingolipid pathway enzyme has the unique role inthese organisms. Various groups have also shown by sphin-golipidomic analysis that several phytoceramide subspeciesincreased in wild type cells after hydroxyurea treatment. Thedeletion of the inositol phosphosphingolipid phospholipaseC gene in S. cerevisiae makes it more sensitive to hydrox-yurea and methyl methanesulfonate and causes arrest ofcell cycle and leads to morphological defects in cell shapes.In Cryptococcus neoformans inositol phosphosphingolipidphospholipase C plays a crucial role in hydroxyurea andmethyl methanesulfonate tolerance. Hydroxyurea also affectthe cell division in inositol phosphosphingolipid phospholi-pase C knockdown cells as compared to wild type cells, thisleads to morphological changes (formation of cell chains andlawns kind of morphology) in inositol phosphosphingolipidphospholipase C depleted cells. Hydroxyurea also affects cellwall synthesis in these pathogens and actin polymerizationduring Cryptococcus neoformans cell division which couldbe a potential drug for treatment of these cells. We alsoobserved that hydroxyurea treatment inhibits the growth ofinositol phosphosphingolipid phospholipase C delta cells in

Journal of Lipids 5

the mouse. This clearly indicates that hydroxyurea treatmentwith inositol phosphosphingolipid phospholipase C deletionhas a synergistic effect and this increasing host survivaloccurs due to decreasing organ fungal load [32]. In the lungof the mouse, hydroxyurea treatment reduced the numberof colony forming units of Cryptococcus neoformans wildtype cells nearly about tenfold from the initial inoculumsas compared to untreated mice. Amazingly on the otherhand the number of colony forming units of Cryptococcusneoformans inositol phosphosphingolipid phospholipase Cdepleted cells decreased more than thousandfold in hydrox-yurea drug treated mice as compared to untreated mice [32].

Leishmania parasites cause a spectrum of diseases verywell-known as leishmaniasis and infect more than twelvemillion people around the world. Leishmania also possessesinositol phosphosphingolipid phospholipase C homolog thatis known as inositol phosphosphingolipid phospholipase C-Like (ISCL). Zhang et al. described that Leishmania parasiteslike cryptococcus inositol phosphosphingolipid phospholi-pase C-Like possesses neutral SMase activity and plays anessential role in sphingolipid degradation and Leishmaniamajor virulence. They also observed that in BALB/c mice,knockdown of inositol phosphosphingolipid phospholipaseC-like completely abolished acute disease pathology. Inositolphosphosphingolipid phospholipase C-like is also necessaryfor the production of IPC but is not indispensable for theproduction of ethanolamine (EtN) [34].

6. Future Directions

It is well-known that after hydroxyurea drug treatmentthe level of inositol phosphosphingolipid phospholipase Cincreases into the cell but the exact mechanism behind thisprocess is not uncovered yet [35]. It will also be interestingto check what happened to inositol phosphosphingolipidphospholipase C after MMS treatment and the biochemicaland molecular mechanism behind this. Activation and reg-ulation of its mammalian homolog N-SMase and its role inDNA damage response are also not well elucidated. Role ofSMases in cancer and drug target could be another interestingarea that is less explored. Another predominantly fascinatingfield in this area is the involvement of fungal sphingolipidpathways in cell signaling and virulence. The role of inositolphosphosphingolipid phospholipase C is not well elucidatedin pathogen like Cryptococcus and Leishmania. It will also beinteresting to know how these pathways play the crucial roleduring DNA replication and checkpoint response. Anotherinteresting area will be to explore the role of its mammalianhomolog in cell division and apoptosis in various cancermodels where it plays a crucial role. Knockdown of inositolphosphosphingolipid phospholipase C in combination withother drugs could be a novel tool for the treatment ofpathogen induced diseases.

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper.

Acknowledgments

The author greatly apologizes to the scientists, biologist,researcher, and colleagues whose works were not cited dueto space limitations. The author is very thankful to Dr. YusufHannun for his useful comments on this paper. The authoris very thankful to Dr. Yusuf Hannun and Dr. B. K. Mohantyfor useful discussion during the author’s work on ISC1. Theauthor is also thankful to Fathima Athar for her valuablesuggestions and proofreading of this review.

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