at1 er odcpe h oeua ehnssta govern that mechanisms molecular the decipher to years the 15 during effort last Considerable proteins. (GABARAP) protein associated rnfr mMi,Germany. Main, am Frankfurt hlp Wild glance Philipp a at interactome LC3 The GLANCE A AT SCIENCE CELL ß 1 or (LC3) 3 chain as known members light six comprises family the Atg8 the ubiquitin-like eukaryotes, the higher biogenesis. this including In and initiation proteins, to autophagosome autophagy orchestrate that Central key Atg8, of modifier lysosome. set distinct the a in is to material pathway autophagosomes, intracellular ubiquitin- targets termed the is which pathway vesicles, autophagy, – latter by The pathways fed pathway. degradation lysosomal partly the two and system with proteasome endowed eukaryotic end, are this To homeostasis. achieve cells constant to cell their a for requires order components in turnover cellular all of synthesis Continuous ABSTRACT Ato o orsodne([email protected]) correspondence for *Author am Frankfurt 60438 Frankfurt, University Germany. Goethe Main, (BMLS), Sciences Life Molecular nttt fBohmsr I oteUiest,TedrSenKi7 60590 7, Theodor-Stern-Kai University, Goethe II, Biochemistry of Institute 04 ulse yTeCmayo ilgssLd|Junlo elSine(04 2,39doi:10.1242/jcs.140426 3–9 127, (2014) Science Cell of Journal | Ltd Biologists of Company The by Published 2014. 1, ,DvdG McEwan G. David *, 2 oeua inln,Bcmn nttt for Institute Buchmann Signaling, Molecular c aiouyi cd(GABA)-receptor- acid -aminobutyric 1 n vnDikic Ivan and 1,2 n h copnigpse,w rsn h urn C protein LC3 autophagy. gaining of for current regulation vital be the the to into continues the insight present and been article has we of Glance which poster, network, a interaction at understanding accompanying Science Cell the our this In and family. advanced protein this of significantly functioning has autophagy h yooe(iuhm ta. 08 aaoaae l,2009; al., et Nakatogawa 2008; double-membraned al., to of et it (Mizushima formation deliver lysosome and the cargo the sequester is degradation. which for process autophagosomes, vesicles, organelles this that and to pathway complexes Central catabolic protein conserved large evolutionary targets an is Autophagy Introduction AIM motif, LIR Atg8, GABARAP, LC3, Autophagy, WORDS: KEY oesai u losre saqaiycnrlsse upon system control quality a conditions. stress as protein extracellular serves cellular and achieving intracellular also in role but vital a homeostasis such, plays As only membrane. subsequently not lysosomal the is autophagy across material cytosol degraded the into This recycled 2007). Klionsky, and Xie 3

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Tsukada 2009; Ohsumi, al., et and functionally (Nakatogawa are eukaryotes which higher of yeast of in date, conserved many using to genes, identification, screens (Atg) the Wattiaux, autophagy-related genetic to 38 and led is however, autophagy Duve in 1990s, content (De defective early mutants fashion cytosolic the random that In a underlying 1966). in view its over neglected, the regarding turned been knowledge solely and of long mechanisms lack has the molecular to importance owing physiological mainly its 1960s, con o n neato atesta a enoitd A omitted. in to S1. been found Table be PubMed had can material interactors on supplementary that Atg8 the reported search partners all of literature interaction list comprehensive any primary the addition, for a In and databases. account conducted STRING article also and interactions currently Mint annotated we Glance BioGRID, largely the the the a of on in is based listed overview at interactome eukaryotes an LC3 Science provide higher established we Cell poster, in (GABARAP, this accompanying proteins In the Atg8 unknown. of proteins of relevance the biological expansion The and (MAP1LC3A, (GABA)-receptor-associated GABARAPL2). GABARAPL1, LC3) LC3C, family LC3B, collectively acid (MAP1LC3) LC3A, and names microtubule-associated 3 respectively, short the MAP1LC3C; chain comprising MAP1LC3B, light has homologs gene protein-1 Atg8-encoding human yeast sole juncture the six (Shpilka crucial Interestingly, recruitment 2012). a cargo al., at et and it formation places autophagosome membrane during autophagosomal the at omnyepotdt oio uohg lxadautophagy and flux autophagy are respectively. monitor inhibition, conjugation captured or LC3–PtdEth the to induction and with exploited behavior together commonly unique degraded This are importantly, the material. they and, with fusion membrane where after isolation from LC3-II) even lysosome, the autophagosomes as LC3 with of associated known of sites remain (also both de-conjugation to proteins the localize LC3 in priming PtdEth-conjugated the functions because PtdEth. also ubiquitin reversible E3 Atg4 is Furthermore, type poster). lipidation enzyme and (see RING LC3 lipidation LC3 ubiquitylation, for their as for process promoting the thus the scaffold – requires to a or ligases PtdEth) similar as of LC3- – acts group GABARAPs the that amino of group the complex and carboxyl and Atg5–Atg12/Atg16 the residue between step Atg7 bond glycine final covalent the enzyme the the The of through E1 Atg3. formation (the mediated enzyme the E2-conjugating is of GABARAP-specific PtdEth action residue. to glycine by concerted C-terminal processed a attachment expose initially to Subsequently, are Atg4 protease members cysteine family the the Atg8 to the ligases, to Similar to ubiquitin orthologs (PtdEth). conjugation covalent phosphatidylethanolamine mammalian their lipid the is membrane autophagy and in Atg8 function their for exert step indispensable An machinery lipid-conjugation The 1. Box lhuhteiiildsoeyo uohg ae akt the to back dates autophagy of discovery initial the Although c -aminobutyric neato ates h I oi saWx sequence, WxxL a is motif LIR The LIR-containing multiple partners. on based established interaction the Atg19, been in yeast then in identified since and first and below) was (see sequence p62/SQSTM1 LIR receptor (AIM) The autophagic motif 2007). Atg8-interacting al., the et yeast as (Pankiv to in referred which commonly (LIR), more region is LC3-interacting contain hydrophobic proteins short LC3-binding a verified experimentally the of region Many LC3-interacting the of Characteristics lhuhterpeiemd fato nitaellrprotein intracellular in action of GABARAP mode entire precise AAA the their machinery-associated of although fusion interaction SNARE ATPase the reported with 2004), the subfamily al., this in is Supporting et as 1998). Leil notion well al., et 2006; as (Legesse-Miller ER-to-Golgi al., transport intra-Golgi in et the participates (Chen GABARAPL2 in membrane For whereas plasma involved complex Golgi processes. the the are from to trafficking receptors GABARAPL1 transmembrane membrane of and with translocation in GABARAP co-purify implicated instance, subfamily GABARAP first to The Gelfand, 1994). was and to Hammarback, reported (Kuznetsov proposed and Atg8 microtubules Mann was 1987; initially to studied and binding 1B extensively their was and influence most 1A date, the protein microtubule-associated LC3B, to 2001). system protein al., nervous GABARAPL1 central et whereas the in lung, (Xin LC3C predominant abundant the are less GABARAPL2 in each et the and example, Wang expression between For 2000; pronounced 2001). al., variations al., has et slight et Sagiv Xin 2000; only 1999; al., al., al., display et (Kabeya et and ubiquitously member Wang expressed family tissues 2000; are al., proteins all These et 2001). in Sagiv al., animals 2000; of et al., metazoan Xin diversification 1999; et in (Kabeya this found plants only with and (Ubls) subfamilies, modifiers GABARAP ubiquitin-like and LC3 oal,bt h oeo h bqii odadN-terminal LC3-mediated and for into fold indispensable ubiquitin cargoes are the extension recognition. autophagic of cargo the core in proteins. of adaptor the residues for activities sites recruitment both docking role Notably, as hemifusion key selective serve a and play and autophagosomes, proteins the LC3 tethering Moreover, in 2011). autophagosomes al., membrane of et size (Weidberg the GABARAP its LC3– control to and biogenesis, through proposed been LC3 autophagosome has GABARAP During other PtdEth LC3C, GABARAPL1). not LC3A, the did (i.e. and of ATG5–ATG12/ATG16L1 however, individually members study, contribution subfamily the This possibly the 2010). of al., address autophagy, et maturation, dissociation (Weidberg of complex GABARAPL2 stage autophagosome the early and involving mediate an downstream, LC3B at further whereas, GABARAPs act of elongation, LC3s addressed autophagosome roles al. during that et suggested distinct Weidberg and manner. potentially redundant autophagy the apparently in participate an proteins in GABARAP the and by LC3 poster). numerous lipids biogenesis and to 1 autophagosome Box conjugated (see during directly machinery conjugation are role ubiquitin-like proteins vital and family these Atg8 a Tsukada the because that 2009; shown play been al., has members it et then, Since (Nakatogawa 1993). crucial Ohsumi, autophagy its highlighting during deleted, is role Atg8 when autophagy et defective Kittler 2000). 2006; al., al., et et Sagiv (Chen 2001; elucidated al., be to remains trafficking oee,teqeto htitiusms eerhr swhy is researchers most intrigues that question the However, functionally to leads yeast in paralogs Atg8 of lack The N ehlaemd-estv uinpoen(NSF), protein fusion -ethylmaleimide-sensitive ora fCl cec 21)17 – doi:10.1242/jcs.140426 3–9 127, (2014) Science Cell of Journal

Journal of Cell Science 08 oae l,20) rpohnrsdei energetically is lower the residue whereas tryptophan residue, al., phenylalanine A et or 2008). tyrosine (Ichimura LIR- over member al., the favored family et of Atg8 Noda pockets) the L 2008; on and (LDS) (W site accommodated pockets docking are position hydrophobic last to two the (for aromatic in appears within The acid 2012). residue amino residues al., aliphatic aromatic et the (Alemu and the determinant charged crucial which most the in negatively be poster) by see examples, preceded N-terminally GLANCE A AT SCIENCE CELL rtisrvae ihycnevdLRmtfi t3ta is this that though, Atg3 Consistently yeast in counterpart. of motif 2010). mammalian LIR the al., autophagy interaction conserved in et highly absent validated core a Yamaguchi revealed functionally 2010; LIR-containing proteins the al., another et Interestingly, is (Behrends component mammals) and remains this of 2012). al., relevance the et functional preferentially than (Alemu the elusive rather members although members proteins, subfamily complex LC3 GABARAP ULK the with ULK that interact the Detailed revealed autophagosome. ensure nascent the analyses that to tethered motifs firmly the is LIR RB1CC1/FIP200 complex addition, functional and In contain (yeast) 2012). 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Atg4, from moiety motif-dependent of lipid the recruitment LIR removing the is al., this et it promote (Satoo lacking, that Atg4 currently of is center conceivable evidence catalytic experimental helps the Although into which 2009). out change, reach LC3- conformational Atg4– to the a LC3B the that revealed undergoes of Atg4 by enzyme structures free bound to Crystal Atg8–LC3B comparison moiety. in PtdEth-conjugated complex PtdEth LC3B retrieves the it off glycine cleaving (2) C-terminal its primes and exposing latter it by The residue PtdEth (1) the to biogenesis: characterized. conjugation and autophagosome for well Atg8 Atg7 during been roles E1-like ATG5, two has the 2010); serves (ATG4, with Atg4 al., LC3 protease et system of cysteine (Behrends interaction lipidation reported the been however, Atg8 have ATG16L1) the ATG7, of other components 2010). delivering all selectively to vacuole. by al., the opposed role to for biosynthetic as enzymes a precursor et serves, autophagy, yeast-specific dispensable pathway of the types (Yamaguchi Cvt but for the Remarkably, autophagy essential pathway, be starvation-induced (Cvt) to appears cytoplasm-to-vacuole sequence LIR neatoso h t8fml ebr ihalother all with members family Atg8 the of Interactions ora fCl cec 21)17 – doi:10.1242/jcs.140426 3–9 127, (2014) Science Cell of Journal Salmonella b 5 -

Journal of Cell Science ufc rtis uha DC rmtfsn become mitofusin, or VDAC1 as such al., 2009). et al., proteins, et autophagic Kanki Okamoto mitochondrial 2010; for 2012; surface outer al., mitophagy, et al., primed Parkin-mediated Novak during 2012; et However, and al., et (Hanna placed Liu mitochondria 2009; membrane already of mitochondrial are outer clearance In BNIP3L are that 2009). BNIP3, mammals) al., proteins yeast; et in Zheng in FUNDC1 2011; (Atg32 and al., receptors et mitophagy Wild contrast, 2009; al., et (Thurston GLANCE A AT SCIENCE CELL ihL3ado AAA rtis B12,truhits through TBC1D25, 6 proteins. Cdc16) GABARAP Bub2, (Tre2, and/or TBC LC3 the with is of consists GAPs proteins which GTPase-activating of family, of is family action GTP One the whereby (GAPs). by activity, GDP- GDP, GTPase Small their into through intrinsic converted off their between 2008). switched of are cycling activation They al., state. the a (‘on’) et GTP-bound through and is (‘off’) activated (Itoh complex and are structures ATG12–ATG5/ATG16 GTPases ATG16L1 the pre-autophagosomal with of to recruitment interacts in PtdIns3 that involved to Rab33B 2010). binding al., Golgi-resident GOLD et and (Pankiv exclusive proteins FYVE motor in the kinesin to results between coupling located and is domains, which and LIR, endosomes W-type phosphatidylinositol late and coiled-coil to (PtdIns3 LC3 3-phosphate with localizes and 2004). interacts 1) and al., (FYVE autophagosomes protein et FYCO1 containing (Gutierrez protein domain overexpressed Rab7-interacting is dominant-negative The endosome/lysosome Rab7 late the GTPase the when small of of form degradation inhibited GDP-bound) example, also is (constitutively the For can substrates GTPases pathway. within autophagy these autophagy fusion of the and some influence Therefore, trafficking pathway. enable interaction, that endocytic GTPases the Rab protein At small pathways. the effector lie both pathways between endocytic of crosstalk possess interaction heart a multiple maturation facilitate share that also endosome such, partners as and and, autophagy resemblances striking of processes The and maturation the trafficking vesicle autophagosome in and involved proteins stimulus) LC3-binding are the members upon family a depending mechanisms. these the molecular require instance, underlying how towards will (for determine specificity members utilized to the family effort elucidate GABARAP concerted clearly and LC3 To different 2010). (Behrends an al., proteins Atg8 or display proteins, et lipid-conjugated Atg7, the difference and Atg8 to no Atg3 affinity including lipid-conjugated decreased either partners, the interaction show 13 15 with whereas that interaction association found GABARAP enhanced proteins, al. GABARAP and and et LC3 LC3 conjugated Behrends or 28 By free remains 2011). either of to al., LC3B partners binding their et with (Shvets the in autophagosomes interaction comparing LC3B to the attached and reported only once GABARAPL2 been intact but has both form, it with as unlipidated interacts specificity, p62 determines could that that conjugation factor LC3 Muhlinen Moreover, interact the (von 2010). to al., LC3B be et shown with Novak 2012; weakly been al., only et for has and optimized BNIP3L is GABARAPL1 the whereas NDP52 with LC3C, in sequence open affect to LIR an binding remains the to still example, members For family issue. shown GABARAP or LC3 been certain mitochondria. has stressed to Parkin BNIP3 of translocation and ubiquitylated h pcfct fteLRmtfi uohg eetr towards receptors autophagy in motif LIR the of specificity The nte ml Taeta sivle natpayi the is autophagy in involved is that GTPase small Another P .Isitrcinwt C smdae ya by mediated is LC3 with interaction Its ). , 6mmes fwih1 a interact can 14 which of members, 36 P and I eune Bridti ta. 03.Teersde r prime are residues These 2013). directly al., in et found (Birgisdottir acid be sequences amino LIR aromatic can 2008). critical al., residues the et threonine Noda preceding 2013; or al., majority serine et acids the (Birgisdottir Additionally, of motifs amino region LIR acidic known flanking of as upstream the notion, predominate LIR this clearly The supports interaction. of LC3–LIR sequence N-terminal the acids complex consensus aid amino in motif acidic core p62/SQSTM1 the hydrophobic of that the revealed motif have LIR LC3 the with of studies Structural of interactions regulation LC3 the in modifications Post-translational uohgcsbtae Mtuooe l,21) aiginto Taking of 2011). degradation al., the et for promoting affinity (Matsumoto its substrates increases thereby p62 autophagic of be cargo, of domain can phosphorylation UBA ubiquitylated substrate example, the within their For Ser403 phosphorylation. with by receptors regulated autophagy of interaction 2010). into al., recruitment et LC3 (Cherra inhibiting by autophagosomes function to been these LC3 appears affect of it have but negatively role investigation LC3B, further physiological needs The and events phosphorylation N-termini. LC3A their of namely within removal identified system, the conjugation enabling Ubl 2012). thus al., et hypoxia, (Liu Atg8, mitophagy under by with mitochondria damaged interact state, occurs or inactive stressed to the an which it in dephosphorylation, it abrogate allows keeps its (YEVL) potentially phosphorylation motif whereas Indeed, LIR could FUNDC1 members. the family site of Atg8 and with this tryptophan, of interaction place at in known residue of tyrosine phosphorylation subset a A contains motifs proteins. LIR LC3-interacting with 2013). interaction al., the et (Zhu apoptosis induces Bnip3 its state Conversely, enhances unmodified clearance. Bnip3, residues its mitochondrial of in in serine/ serine motif resulting LIR (Farre both Atg8, Atg36 the to of of flank binding motifs that phosphorylation and Ser24) LIR phosphorylation and the (Ser17 their addition, Atg32 to by In yeast 2013). adjacent the receptors, regulated residues Similarly, N-terminal threonine are pexophagy 2013). the al., in respectively, and et Arg11 (Rogov and mitophagy LC3B makes Lys51 of group its phosphate with extension charged enhances contacts negatively 178–181) the additional confirmed that studies was at showed crystallography which and that is 2011), (NMR) resonance al., magnetic LIR et nuclear by (Wild (the LC3B of can with Ser177 phosphorylation interaction (McEwan that that shown at manner have compartmentalized receptors we optineurin Indeed, a 2011). autophagy in Dikic, and of and regulated rapidly inactivation) proceed (PTM) (or modification activation post-translational for candidates Ppvce l,2012). al., autophagy increasing et starvation-induced by (Popovic and switch trafficking out-competed molecular endosomal a be as between TBC1D5 of can with, implicating component LC3, and a of co-localization concentrations VPS29, Interestingly, complex, with 2012). retromer interact and also al., the can to, et LIR N-terminal (Popovic binding its proteins are both Atg8 efficient and C-terminus mammalian the for at motifs, other the LIR required and two N-terminus contains the TBC1D5 and at 2011). trafficking one al., retrograde et in of (Itoh involved Rab33B maturation is towards homologs activity Atg8 the GAP with its regulate interaction and direct can a Rab33B, through autophagosomes towards activity GAP neetnl,ntol h I–C neato u lothe also but interaction LIR–LC3 the only not Interestingly, autophagy the of members two in sites phosphorylation note, Of abrogate also can motif LIR the of phosphorylation Importantly, ora fCl cec 21)17 – doi:10.1242/jcs.140426 3–9 127, (2014) Science Cell of Journal , 5 fidentified of 25% ´ tal., et

Journal of Cell Science jrø,G,Lmr,T,Beh . uzn . eadr . vran A., Overvatn, M., Perander, H., Outzen, A., Brech, T., W. Lamark, J. G., Harper, Bjørkøy, and T. P. Johansen, and T. S. Lamark, B., Gygi, A. Birgisdottir, E., M. Sowa, C., Behrends, D. Kang, and T. Uchiumi, T., Saigusa, Y., Kurihara, Y., Hirota, T., Kanki, Y., Aoki, B., K. Larsen, B., A. Birgisdottir, M., K. Torgersen, T., Lamark, A., E. Alemu, euaetertafcig uclua oaiainand/or localization perspectives and and Conclusions subcellular fold ubiquitin trafficking, a harbor that degradation. their LC3–LIR proteins to regulate of binding and phosphorylation mechanism control general that a to constitute UBDs SUMO–SIM conceivable as well therefore as motifs Ubl-binding above-discussed is it interactions, the account GLANCE A AT SCIENCE CELL les . rn,H,Kbr . asr . ln,M,Sco,J,Kr,R and R. Kern, J., Suckow, M., Klink, C., Kaiser, I., Kober, H., Kranz, M., Albers, Fro S., P. Aguilar, References at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.140426/-/DC1 online available material Supplementary material Supplementary as available online are http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.140426/-/DC2 the panels in poster at Individual downloading files jcs.biologists.org. for JPEG at available article is this poster of the version of version high-resolution glance A a at science Cell interests. competing no declare authors The I.D. interests to agreement Competing and grant D.G.M (ERC) (to Council Frankfurt Research therapy European Cell an and and University Gene I.D.); Goethe for the Centrum the of LOEWE Forschungsgemeinschaft; Complexes’ Frankfurt; Deutsche ‘Macromolecular from Excellence the grants of by Cluster of supported was role work This the deciphering Funding at autophagy. aimed in proteins be LC3/GABARAP individual should studies Thus, the specialization. functional future to and most regard redundancy which with both eukaryotes, reflects higher knowledge likely in of family lack Atg8 the clear stress of a diversification various also mitochondrial under is damage, There and DNA PTM-driven stress). hypoxia, space, starvation, and elucidating (e.g. LC3- time the conditions determine fully in far in to network effort is particular, substantial interaction interest network a require LC3 in overshadowing will currently presented interactions complete; the the are this, from of which said LC3 Having functions, because autophagy-unrelated autophagy. their less is neglect It and investigated not pathway. partners this to towards interacting bias current important the strong autophagy, a therefore to family bears this interactome link LC3 not did proteins of LC3 that studies the first substantiated mind very been the in yet Although functionally. not bear and/or have Harperbiochemically should interactions the reported One these by 2010). of conducted many al., been et has (Behrends laboratory that network high- GABARAP LC3 mammalian from and the stems particular in interactome and LC3 studies interaction assembled throughput the of majority The tnak .adJhne,T. 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