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Mammalian Macroautophagy at a Glance

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Mammalian Macroautophagy at a Glance Cell Science at a Glance 1707 Mammalian been implicated in several human diseases, pathways, and we will address the ever- such as cancer, certain neurodegenerative growing roles of autophagy in human macroautophagy at disorders and infectious diseases. physiology and pathology. a glance Although autophagy is thought to be predominantly a cell-survival mechanism, Autophagy machinery Brinda Ravikumar, Marie Futter, some evidence points towards a role in cell The foundation for understanding the Luca Jahreiss, Viktor I. death. Our understanding of mammalian mammalian autophagy machinery was Korolchuk, Maike Lichtenberg, autophagy, in terms of the molecular provided by a series of genetic screens in Shouqing Luo, Dunecan C. O. machineries and signalling cascades that the yeast Saccharomyces cerevisiae; these Massey, Fiona M. Menzies, Usha are involved in its regulation, has grown screens identified around 30 so-called Narayanan, Maurizio Renna, considerably over the last few years. In autophagy-related (ATG) genes that are Maria Jimenez-Sanchez, Sovan particular, there has been an explosion of required for autophagy (Xie and Klionsky, Sarkar, Benjamin Underwood, data in the last 3 years trying to address the 2007). About half of these genes have Ashley Winslow and David C. importance of mammalian autophagy in obvious mammalian counterparts, and Rubinsztein* physiology and pathophysiology. Here, we many of the core aspects of the process are Department of Medical Genetics, Cambridge aim to summarise the recent advances in conserved. It is possible that some genes Institute for Medical Research, Addenbrooke’s mammalian macroautophagy in terms of that do not have obvious orthologues in Hospital, Hills Road, Cambridge CB2 0XY, UK *Author for correspondence (e-mail: its regulation, which will include newly mammals still exist but have been missed, [email protected]) identified molecules and signalling as there might be structural and functional Journal of Cell Science 122, 1707-1711 Published by The Company of Biologists 2009 doi:10.1242/jcs.031773 Autophagy refers to a set of non-specific bulk degradation processes in which cells deliver cytoplasmic substrates for lysosomal degradation. Types of autophagy include macroautophagy, chaperone-mediated autophagy and microautophagy. Chaperone-mediated autophagy is selective for specific cytosolic proteins that contain a pentapeptide motif. This motif is recognised by the chaperone heat shock Journal of Cell Science cognate 70 (Hsc70), which transfers protein substrates to the lysosomal membrane where, through binding to the receptor lysosome-associated membrane protein 2A (LAMP2A), they are translocated into the lysosomal lumen and degraded. In microautophagy, lysosomes can also directly engulf cytoplasm by invagination, protrusion and/or septation of the lysosomal limiting membrane. The focus of this poster article, however, is mammalian macroautophagy. Macroautophagy (referred to here as autophagy) is a process in which cells form double-membrane vesicles, called autophagosomes, around a portion of cytoplasm. These autophagosomes ultimately fuse with lysosomes, resulting in degradation of their contents. Autophagy is upregulated under physiological stress conditions such as starvation. However, mammalian cells undergo autophagy at a basal level that might be important for the clearance of normally occurring, misfolded, ubiquitylated proteins. Autophagy has also (See poster insert) 1708 Journal of Cell Science 122 (11) orthology without obvious sequence conjugated to PE to form membrane- manner to lysosomes, which are clustered similarity. associated LC3-II, a process that requires around the microtubule-organising centre the activities of Atg7 (E1-like) and Atg3 (MTOC; located near the nucleus). There, Initiation of autophagosome formation (E2-like) (Ohsumi and Mizushima, 2004). autophagosomes tether, dock and fuse with Autophagosome formation appears to start The Atg5-Atg12 conjugate seems to lysosomes, and the contents of the two at phagophore (autophagosome precursor; modulate LC3-I conjugation to PE by vesicles are mixed (Jahreiss et al., 2008). also known as pre-autophagosomal acting in an E3-like fashion (Hanada et al., The details of this aspect of mammalian structures)-assembly sites (PAS). The 2007) and the Atg5-Atg12-Atg16L autophagy are still unclear, although the source of the membrane is unclear, complex also determines the sites of LC3 SNARE proteins that are involved in yeast although recent data support a contribution lipidation (Fujita et al., 2008). In this way, autophagosome-vacuole fusion have been from the endoplasmic reticulum (ER) (Axe LC3 is specifically targeted to Atg5- characterised (Ishihara et al., 2001). et al., 2008). The formation of the Atg12-associated membranes, which are En route to fusion with the lysosomes, phagophore requires the activity of the expanded phagophores. autophagosomes can fuse with endosomes class-III phosphoinositide 3-kinase (PI3K) to form amphisomes. It is currently not Vps34, which forms phosphatidylinositol Crosstalk between the two ubiquitylation- clear whether amphisome formation is a 3-phosphate [PtdIns(3)P]. Chemical like systems has also been suggested. prerequisite for autophagosome-lysosome inhibition of Vps34 by 3-methyladenine or Atg10 can interact with LC3-I and fusion. Reduced activity of some ESCRT wortmannin blocks the formation of new facilitate LC3-I conjugation to PE (endosomal sorting complex required autophagosomes. Vps34 is part of a large (Nemoto et al., 2003). Similarly, Atg3 for transport) proteins disrupts macromolecular complex specific for co-immunoprecipitates with Atg12, and autophagosome-lysosome fusion, resulting autophagy that contains the proteins Atg6 overexpression of Atg3 increases Atg5- in the accumulation of autophagosomes (also called beclin 1), Atg14 and Vps15 Atg12 conjugation (Tanida et al., 2002). (Skibinski et al., 2005). Similarly, LAMP2 (p150) (Itakura et al., 2008). Other proteins Although Atg5-Atg12 is lost upon deficiency has been associated with the that are involved in the initiation stage of completion of autophagosome formation, accumulation of autophagosomes, which is autophagosome formation include Atg5, LC3-II remains associated with consistent with a defect in fusion Atg12, Atg16, the newly identified autophagosomes even after fusion (Eskelinen et al., 2002). autophagy-related protein focal adhesion with lysosomes, after which LC3-II on the kinase (FAK)-family interacting protein of cytosolic face of autolysosomes can be Signals for autophagosome 200 kD (FIP200), which interacts with delipidated and recycled (to LC3-I). formation Atg1 (also called ULK1) (Hara et al., Conjugated LC3 is a substrate for Atg4, mTOR-dependent pathway 2008), and the mammalian orthologue of and Atg4 delipidates LC3-II and removes One of the classical pathways that regulate Atg13 (Chan et al., 2009; Hosokawa et al., it from the membrane. Furthermore, the autophagy is controlled by the mammalian 2009; Jung et al., 2009). production of reactive oxygen species target of rapamycin (mTOR). mTOR (ROS; specifically H2O2) during starvation activity inhibits mammalian autophagy, Journal of Cell Science Autophagosome elongation results in oxidation and inactivation of but its activity is inhibited under starvation Atg5 and Atg12 are involved in the first of Atg4. This inhibits LC3-II delipidation and conditions, which contributes to two ubiquitylation-like reactions that might promote autophagosome formation starvation-induced autophagy. Autophagy control autophagy. Atg12 is conjugated to (Scherz-Shouval et al., 2007). is also induced by inhibiting mTOR with Atg5 in a reaction that requires Atg7 drugs such as rapamycin (Rubinsztein et [ubiquitin-activating-enzyme (E1)-like] LC3-II is the only known protein that al., 2007). Mammalian Atg13, ULK1 and and Atg10 [ubiquitin-conjugating-enzyme specifically associates with autophago - ULK2 have recently been identified as (E2)-like]. Atg5-Atg12 conjugates are somes and not with other vesicular direct targets of mTOR (Chan et al., 2009; localised onto the PAS and dissociate upon structures. Thus, LC3-II levels correlate Hosokawa et al., 2009; Jung et al., 2009). completion of autophagosome formation. with autophagic vacuole numbers, which Atg13 binds to ULK1 and ULK2 The process of Atg5-Atg12 conjugation can also be assessed by scoring LC3- (ULK1/2) and mediates their interaction depends on Vps34 function, and Vps34 positive vesicle numbers (Kabeya et al., with FIP200. Under nutrient-rich activity, along with autophagy, is positively 2000). LC3-II can mediate membrane conditions, mTOR is associated with this regulated by the small GTPase Rab5 tethering and hemifusion, and these complex. Inhibition of mTOR leads to its (Ravikumar et al., 2008). Atg5-Atg12 functions might be crucial for the dissociation from the complex and results interacts non-covalently with Atg16L expansion of autophagosome membranes. in the partial dephosphorylation of Atg13 (Atg16-like) to form a complex of These data also raise the possibility that and ULK1/2; this activates ULK1/2 to approximately 800 kDa (Ohsumi and LC3 assists the final fusion of the pre- phosphorylate FIP200 and thereby induce Mizushima, 2004). autophagosomal double-membrane ‘cups’ autophagy (Chan et al., 2009; Hosokawa into fused vesicles (Nakatogawa et al., et al., 2009; Jung et al., 2009). The second ubiquitylation-like reaction 2007). involves the conjugation of microtubule- Several signalling molecules regulate
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