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Simonsen for Sven Anne by biogenesis’ sites autophagosome ( Sanchez- in ‘ERES: dynamics Jana al. articles: by et maturation?’ related Wandelmer and For see biogenesis. biogenesis Autophagosome please autophagosome on Focus reading, a of further part is article This autophagy. in rational WIPI1–4, proteins, for WIPI of human roles targets four the on the novel knowledge current present the summarize might we Here, proteins therapies. and and neurodegeneration, and cancer WIPI in compromised be to appears PtdIns3 The homolog. autophagy-specific as function PtdIns3 hence and autophagosome, PtdIns3 nascent the decoding and recognizing in role important WD- as an play human known family the (WIPI) phosphoinositides (also with of interacting Members p150 repeat ATG14L. 1, and yeast) beclin in with Vps15 complex PIK3R4; 3-phosphate in PIK3C3) phosphatidylinositol as known of production (PtdIns3 the autophagosome for is essential formation for and compartment Prerequisite lysosomal degradation. the dynamical cargo from hydrolases acidic in acquire organelles, and and by lipids functioning proteins, including executed sequester material, Autophagosomes cargo proteins cytoplasmic autophagosomes. and form initiated (ATG) to hierarchies is related and autophagy destruction, cargo and specific or stochastic recognition by cytoplasm including the clears autophagy) pathologies, as to referred human (hereafter Macroautophagy age-related neurodegeneration. and of cancer of development lifespan the immunity the to determines contributes development, crucially also and autophagy However, in organisms. pathogens, eukaryotic against roles defence cellular essential and secures that fulfills process cytoprotective homeostasis, pivotal a is Autophagy ABSTRACT bradKrsUiest ubne,Seant.3 9 27 Tuebingen, 72076 39, – and 35 Biology Spemannstr. Developmental Germany. Tuebingen, for University Institute Karls Planck Eberhard Max Organisms’, to Molecules Ato o orsodne([email protected]) correspondence for *Author Germany. University Tuebingen, Karls 72076 Eberhard 14, Science, Sand Computer of Tuebingen, Department and Center, Biology uohg aoaoy eateto oeua ilg,Itraut nttt of Institute Interfaculty Biology, Molecular of Department Laboratory, Autophagy 05 ulse yTeCmayo ilgssLd|Junlo elSine(05 2,2727doi:10.1242/jcs.146258 207–217 128, (2015) Science Cell of Journal | Ltd Biologists of Company The by Published 2015. P P 3 bnigefcos iia oteracsrlyatAtg18 yeast ancestral their to similar effectors, -binding ple iifraisGop etrfrBonomtc,Quantitative Bioinformatics, for Center Group, Bioinformatics Applied ypopaiyioio -iaecasII(IK3 also (PI3KC3, III class 3-kinase phosphatidylinositol by ) .Cl Sci. Cell J. .Cl Sci. Cell J. 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I20popoyain L1siuae PtdIns3 stimulates ULK1 phosphorylation, or FIP200 2004), either Dubbelhuis, Kim 2011; and al., levels 2011). al., et al., Meijer (Egan et et ATP 2008; phosphorylation ULK1 al., (Corradetti through cellular directly, et inactivation low Gwinn AMPK, mTORC1 activates 2004; to pathways, through initiation. contrast, response catabolic By indirectly, towards in 2011). autophagy switch al., autophagy et a permits Kim as 2009; functioning starvation al., et Jung nutrient Hosokawa 2009; 2009; al., al., et (Ganley et RB1CC1) as and known and serine/ ATG13 (also with FIP200 with a complexes that ULK1, associating kinase protein protein threonine-specific by autophagy-related al., autophagy RHEB the et (Dennis phosphorylating inhibits through proteins RAG mTORC1 factors anabolic through acids 2011), growth towards amino by by switch or mTOR proteins, activated essential the When an availability through pathways. 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ATG-18, of downstream seven-bladed a encodes WDR45) as known (also WIPI4 hw ob seta o uohg nmmaincls The cells. mammalian in in autophagy of EPG-6 was for homolog number the WIPI4 essential WIPI4 Thus the be 2011). impaired to al., increased shown et and (Lu WIPI4 phagophores autophagosomes ATG5-positive of of formation downregulation as formation, for autophagosome siRNA-mediated essential and not be maturation unpublished to was omegasome found Robenek, proper WIPI4 was Horst WIPI4 WIPI2, Functionally, and to observations). and (T.P.-C. fracture (Lu immunofreeze microscopy WIPI1 by relocates LC3 analyzed electron unlike as autophagosomes with but WIPI4 on found 2011), al., colocalizes et starvation, al., and (Lu et cells upon membranes dividing in autophagosomal of Specifically and pattern cells, diffuse localization (NRK) a 2011). kidney The shows rat normal expression protein 2004). in the initial analyzed al., been an in to has overexpressed in et WIPI4 be bind samples (Proikas-Cezanne to cancer specifically analysis appears kidney in and and to levels heart, high pancreatic and expected at muscle expressed is ubiquitously skeletal is that it phosphoinositides; protein propeller of role functional the and yet, as unknown. demonstrated is this WIPI3 been however, not 2004); al., has et (Proikas-Cezanne phosphoinositides tiigy II a on ob mutated be to found was WIPI4 Strikingly, WIPI4 ee hc rbbyrsl ntepouto of production the in result probably which gene, b poelrta pcfclybnsto binds specifically that -propeller WIPI4 .elegans C. eei oaie nteX the on localized is gene stogtt function to thought is enovo de enovo de mutations P and b at - is ieteiec htatpaymlucini astv of 2013). al., causative Moreover, et is the (Saitsu malfunction provides humans SENDA. autophagy in patients that neurodegeneration of SENDA evidence direct in classification both first mutations for WIPI4 and importance identifying utmost diagnosis of are future findings These degradation. fWP rtiscudhl oeuiaetepicpe of principles the elucidate to help could understanding proteins better misregulated a mutations WIPI Hence, WIPI or neurodegeneration. of of and defective identification variety cancer the exhibit great in by a indicated that in as pathologies compromised autophagy, be human to likely of WIPI of is function the members autophagy, in family role important their of basis On the formation. membrane autophagosomal of and understanding initiation should autophagy the regulation of for understanding further and nascent the for action the clues concerted hold at members their WIPI decipher as to the autophagosome, interest of urgent contributions of individual is It the LC3. of downstream anticipated function is ATG12–ATG5–ATG16L1to also and ATG2 is with interacts the WIPI1 WIPI4 addition, which In for recruits essential. lipidation, LC3 WIPI2 mediates which means, complex, this By uohgsm omto nhat n disease. and health in formation autophagosome vdnesget htWP1 II n II ucinas function WIPI4 PtdIns3 PtdIns3 and PI3KC3-mediated non-redundant WIPI2 and WIPI1, essential that suggests Evidence Conclusions ini,A . adl,N,Ksan .S,Gnrs .C,Muthuswamy, C., M. 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