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NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 2 | JULY 2001 | 491

In the Golgi, mannose-6-phosphatereceptors (M6PRs) grab newly synthe-sized lysosomal hydrolases by theirsugars to whizz them to their final des-tination, lysosomes. But how do thereceptors themselves know where togo? Two groups now report in Sciencethat the GGA coat adaptors showthem the way.

The lysosomal sorting signal wasidentified almost a decade ago — anacidic cluster followed by a dileucinemotif in the cytoplasmic tail of theM6PR. The AP-1 adaptor complexwas the prime suspect for bindingM6PRs and assembling the clathrincoat. It now turns out that it is, in fact,the most recently discovered adaptors— the GGAs (for Golgi-localized, γ-ear-containing,ARF-binding) — thatbind to the lysosomal targeting signalsof M6PRs and sort them to lysosomes.

GGAs are made of four domains: aVHS domain; a GTP–ARF-bindingdomain (GAT); a hinge that containsbinding sites for clathrin; and a GAEdomain that interacts with γ-synerginand other regulators of coat assembly.The sorting signals of M6PRs interact-ed specifically with the VHS domainsof GGAs in two-hybrid assays, in pull-down assays and by surface plasmonresonance spectroscopy. Specifically,the cation-independent M6PR boundall three human GGAs, whereas the

cation-dependent M6PR preferredGGA1 over GGA3, and did not bindGGA2. Immunofluorescence studiesshowed that M6PRs and GGA1 colo-calize in the trans-Golgi network(TGN) and in the cell periphery, andtime-lapse imaging of live cellsrevealed that GGA1 associates withtubules and vesicles that bud from theTGN.

Kornfeld and colleagues show thatthere is a correlation between reducedin vitro binding of the cation-inde-pendent MPR to GGA2 and mis-sort-ing of lysosomal enzymes. Last,Bonifacino and colleagues provideevidence for a functional involvementof GGAs in sorting of M6PRs, as over-expression of a dominant-negativeGGA1 construct blocks exit of thecation-dependent M6PR from theTGN.

So GGAs probably function asadaptors between M6PRs, ARF,clathrin and regulators of coat assem-bly. But do they recruit receptors intoAP-1–clathrin vesicles or do they buildclathrin-coated vesicles of their own?

Raluca GagescuReferences and links

ORIGINAL RESEARCH PAPERS Puertollano, R.et al. Sorting of mannose 6-phosphate receptorsmediated by the GGAs. Science 292, 1712–1716(2001) | Zhu, Y. et al. Binding of GGA2 to thelysosomal enzyme sorting motif of the mannose 6-phosphate receptor. Science 292, 1716–1718(2001)

yeast MSH2 that occur in humanMSH2 in hereditary nonpolyposiscolorectal cancer. These mutationsenhanced survival of a telomerase-defective strain to a similar extent asMSH2 deletion. Inactivatingtelomerase and mismatch repair inanother yeast, Kluyveromyces lactis— with a pattern of telomeresequence degeneracy similar to thatfound in human cells — yieldedsimilar results, indicating that theseobservations may indeed extrapolateto events occurring in mismatchrepair-defective human cells.

These experiments raise manyquestions for cancer research. Dohuman telomeres undergo morerecombination in the absence of

mismatch repair? Can mismatchrepair-defective cancer cells get bywithout telomerase? What is therelative importance of mutationversus telomere maintenance inthese cells? And can we developtherapeutics that reduce mismatchrepair-defective cells back to thestatus of mere mortals?

Cath BrooksbankEditor, Nature Reviews Cancer

References and linksORIGINAL RESEARCH PAPER Rizki, A. &Lundblad, V. Defects in mismatch repairpromote telomerase-independent proliferation.Nature 411, 713–716 (2001)FURTHER READING Kucherlapati, R. &DePinho, R. A. Telomerase meets its mismatch.Nature 411, 647–648 (2001)WEB SITE Mismatch repair

Giga-sorting in the Golgi

P R OT E I N S O RT I N G IN BRIEF

Impairment of the ubiquitin–proteasome system byprotein aggregation. Bence, N. F. et al. Science 292, 1552–1555 (2001)

Protein aggregates are a prominent feature of manyneurodegenerative diseases. But are these aggregates a cause or aconsequence of neurotoxicity? The authors show here thatoverexpression of proteins that are prone to aggregation — eitherin pericentriolar aggresomes or in amyloid-like fibrils — inhibitsthe ubiquitin–proteasome system. As proteasomal degradation isessential for cell survival, inhibition of this cellular system byprotein aggregation is highly pathogenic.

Specific targeting of insect and vertebrate telomereswith pyrrole and imidazole polyamides.Maeshima, K. et al. EMBO J. 20, 3218–3228 (2001)

The authors report new cell-permeant compounds — polyamidescontaining two, flexibly linked, hairpin DNA-binding moieties —that specifically target telomeres. Fluorescent analogues of thesecompounds colocalize with the telomere-binding proteins TRF1and TRF2. These drugs provide a convenient alternative tocurrent cumbersome methods for estimating telomere length.Polyamides of this type could become useful tools for telomereresearch, and might even have potential as medicinal agents.

Sensitive detection of pathological prion protein bycyclic amplification of protein misfolding.Saborio, G. P. et al. Nature 411, 810–813 (2001)

The infectious prion protein, PrPSc, is thought to work bycatalysing the conversion of the cellular glycoprotein PrPC into itsinfectious form. So far, although there is evidence that prions arepresent in body fluids, it has proved difficult to detect theinfectious prion in patients before death. Here, Saborio et al. useultrasound to free prions from plaques in vitro, which speeds upthe conversion cycle. This might allow diagnosis of the presence ofinfectious prions in the bloodstream.

G-protein signalling through tubby proteins.Santagata, S. et al. Science 292, 2041–2050 (2001)

Loss of tubby function leads to obesity. In this study, tubby isshown to act downstream of G-protein-coupled-receptors topotentially regulate gene transcription. Tubby localizes to theplasma membrane by interacting, through its carboxy-terminal‘tubby’ domain, with phosphatidylinositol-4,5-bisphosphate(PtdIns(4,5)P

2). However, activation of Gα

q-coupled receptors

leads to PtdIns(4,5)P2 hydrolysis — probably by increasing

phospholipase Cβ activity. Tubby then translocates to the nucleus,where it might influence genes involved in energy homeostasis.

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