Macroautophagy (hereafter autophagy) is currently one of the areas of medical life sciences attracting a great interest because of its pathological implications and therapy potentials. The discovery of the autophagy-related genes (ATGs) has been the key event in this research field because their study has led to the acquisition of new knowledge about the mechanism of this transport pathway. In addition, the investigation of these genes in numerous model systems has revealed the central role that autophagy plays in maintaining the cell homeostasis. This process carries out numerous physiological functions, some of which were unpredicted and thus surprising. Here, we will review some of the questions about the mechanism and function of autophagy that still remain unanswered, and new ones that have emerged from the recent discoveries. 1. Introduction The basic mechanism of autophagy is the sequestration of the structure that has to be degraded by large cytoplasmic double-membrane vesicles called autophagosomes. The current model is that autophagosomes are formed by expansion and sealing of a small cistern known as the phagophore or isolation membrane (Figure 1) [1–5]. Once complete, they fuse with the mammalian lysosomes or plant and yeast vacuoles to expose their cargo to the hydrolytic interior of these compartments for degradation. In mammalian cells, this event is preceded by the fusion with vesicles of the endocytic pathway and/or endosomes, to form amphisomes (Figure 1) [6]. The metabolites generated in the lysosomes/vacuoles are subsequently transported in the cytoplasm and used as either an energy source or building blocks for the synthesis of new macromolecules. The phagophore is generated at a specialized site known as the phagophore assembly site or preautophagosomal structure (PAS) [1–5]. At this location, the key actors of this pathway, the autophagy-related genes (ATGs), mediate the formation of the phagophore and its expansion into an autophagosome. Sixteen Atg proteins compose the conserved core Atg machinery that catalyses the formation of autophagosomes in all eukaryotes. The rest of the Atg proteins are organism-specific and most of them are involved in either the regulation of autophagy or dictating the specificity during selective types of autophagy. Autophagy has been considered for long time a nonselective process for bulk degradation of either long-lived proteins or cytoplasmic components during nutrient deprivation. Recent evidences, however, have revealed the existence of numerous types of selective autophagy used by the cell to
References
[1]
N. Mizushima, T. Yoshimori, and Y. Ohsumi, “The role of Atg proteins in autophagosome formation,” Annual Review of Cell and Developmental Biology, vol. 27, pp. 107–132, 2011.
[2]
H. Nakatogawa, K. Suzuki, Y. Kamada, and Y. Ohsumi, “Dynamics and diversity in autophagy mechanisms: lessons from yeast,” Nature Reviews Molecular Cell Biology, vol. 10, no. 7, pp. 458–467, 2009.
[3]
Z. Xie and D. J. Klionsky, “Autophagosome formation: core machinery and adaptations,” Nature Cell Biology, vol. 9, no. 10, pp. 1102–1109, 2007.
[4]
Z. Yang and D. J. Klionsky, “Mammalian autophagy: core molecular machinery and signaling regulation,” Current Opinion in Cell Biology, vol. 22, no. 2, pp. 124–131, 2010.
[5]
T. Yoshimori and T. Noda, “Toward unraveling membrane biogenesis in mammalian autophagy,” Current Opinion in Cell Biology, vol. 20, no. 4, pp. 401–407, 2008.
[6]
T. E. Hansen and T. Johansen, “Following autophagy step by step,” BMC Biology, vol. 9, article 39, 2011.
[7]
F. Reggiori, M. Komatsu, K. Finley, and A. Simonsen, “Autophagy: more than a nonselective pathway,” International Journal of Cell Biology, vol. 2012, Article ID 219625, 18 pages, 2012.
[8]
C. He and D. J. Klionsky, “Regulation mechanisms and signaling pathways of autophagy,” Annual Review of Genetics, vol. 43, pp. 67–93, 2009.
[9]
R. A. Nixon and D. S. Yang, “Autophagy failure in Alzheimer's disease-locating the primary defect,” Neurobiology of Disease, vol. 43, no. 1, pp. 38–45, 2011.
[10]
B. Levine, “Cell biology: autophagy and cancer,” Nature, vol. 446, no. 7137, pp. 745–747, 2007.
[11]
B. Levine and G. Kroemer, “Autophagy in the pathogenesis of disease,” Cell, vol. 132, no. 1, pp. 27–42, 2008.
[12]
N. Mizushima, B. Levine, A. M. Cuervo, and D. J. Klionsky, “Autophagy fights disease through cellular self-digestion,” Nature, vol. 451, no. 7182, pp. 1069–1075, 2008.
[13]
H. W. Virgin and B. Levine, “Autophagy genes in immunity,” Nature Immunology, vol. 10, no. 5, pp. 461–470, 2009.
[14]
A. Fleming, T. Noda, T. Yoshimori, and D. C. Rubinsztein, “Chemical modulators of autophagy as biological probes and potential therapeutics,” Nature Chemical Biology, vol. 7, no. 1, pp. 9–17, 2011.
[15]
M. García-Arencibia, W. E. Hochfeld, P. P. C. Toh, and D. C. Rubinsztein, “Autophagy, a guardian against neurodegeneration,” Seminars in Cell and Developmental Biology, vol. 21, no. 7, pp. 691–698, 2010.
[16]
P. Grumati, L. Coletto, P. Sabatelli et al., “Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration,” Nature Medicine, vol. 16, no. 11, pp. 1313–1320, 2010.
[17]
M. T. Rosenfeldt and K. M. Ryan, “The role of autophagy in tumour development and cancer therapy,” Expert Reviews in Molecular Medicine, vol. 11, article e36, 2009.
[18]
D. C. Rubinsztein, J. E. Gestwicki, L. O. Murphy, and D. J. Klionsky, “Potential therapeutic applications of autophagy,” Nature Reviews Drug Discovery, vol. 6, no. 4, pp. 304–312, 2007.
[19]
S. Turcotte and A. J. Giaccia, “Targeting cancer cells through autophagy for anticancer therapy,” Current Opinion in Cell Biology, vol. 22, no. 2, pp. 246–251, 2010.
[20]
H. E. J. Polson, J. de Lartigue, D. J. Rigden et al., “Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation,” Autophagy, vol. 6, no. 4, pp. 506–522, 2010.
[21]
Q. Lu, P. Yang, X. Huang et al., “The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes,” Developmental Cell, vol. 21, no. 2, pp. 343–357, 2011.
[22]
T. Proikas-Cezanne, S. Waddell, A. Gaugel, T. Frickey, A. Lupas, and A. Nordheim, “WIPI-1α (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy,” Oncogene, vol. 23, no. 58, pp. 9314–9325, 2004.
[23]
T. Shpilka, H. Weidberg, S. Pietrokovski, and Z. Elazar, “Atg8: an autophagy-related ubiquitin-like protein family,” Genome Biology, vol. 12, no. 7, article 226, 2011.
[24]
Y. Kabeya, N. Mizushima, A. Yamamoto, S. Oshitani-Okamoto, Y. Ohsumi, and T. Yoshimori, “LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation,” Journal of Cell Science, vol. 117, no. 13, pp. 2805–2812, 2004.
[25]
A. Matsuura, M. Tsukada, Y. Wada, and Y. Ohsumi, “Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae,” Gene, vol. 192, no. 2, pp. 245–250, 1997.
[26]
T. Funakoshi, A. Matsuura, T. Noda, and Y. Ohsumi, “Analyses of APG13 gene involved in autophagy in yeast, Saccharomyces cerevisiae,” Gene, vol. 192, no. 2, pp. 207–213, 1997.
[27]
Y. Kabeya, T. Kawamata, K. Suzuki, and Y. Ohsumi, “Cis1/Atg31 is required for autophagosome formation in Saccharomyces cerevisiae,” Biochemical and Biophysical Research Communications, vol. 356, no. 2, pp. 405–410, 2007.
[28]
Y. Kamada, T. Funakoshi, T. Shintani, K. Nagano, M. Ohsumi, and Y. Ohsumi, “Tor-mediated induction of autophagy via an Apg1 protein kinase complex,” The Journal of Cell Biology, vol. 150, no. 6, pp. 1507–1513, 2000.
[29]
T. Kawamata, Y. Kamada, K. Suzuki et al., “Characterization of a novel autophagy-specific gene, ATG29,” Biochemical and Biophysical Research Communications, vol. 338, no. 4, pp. 1884–1889, 2005.
[30]
C. Kraft, M. Kijanska, E. Kalie et al., “Binding of the Atg1/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy,” The EMBO Journal, vol. 31, pp. 3691–3703, 2012.
[31]
C. A. Mercer, A. Kaliappan, and P. B. Dennis, “A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy,” Autophagy, vol. 5, no. 5, pp. 649–662, 2009.
[32]
G. Thomas and M. N. Hall, “TOR signalling and control of cell growth,” Current Opinion in Cell Biology, vol. 9, no. 6, pp. 782–787, 1997.
[33]
E. Y. Chan, “MTORC1 phosphorylates the ULK1-mAtg13-FIP200 autophagy regulatory complex,” Science Signaling, vol. 2, no. 84, article pe51, 2009.
[34]
N. Hosokawa, T. Hara, T. Kaizuka et al., “Nutrient-dependent mTORCl association with the ULK1-Atg13-FIP200 complex required for autophagy,” Molecular Biology of the Cell, vol. 20, no. 7, pp. 1981–1991, 2009.
[35]
C. H. Jung, C. B. Jun, S. H. Ro et al., “ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery,” Molecular Biology of the Cell, vol. 20, no. 7, pp. 1992–2003, 2009.
[36]
N. Mizushima, “The role of the Atg1/ULK1 complex in autophagy regulation,” Current Opinion in Cell Biology, vol. 22, no. 2, pp. 132–139, 2010.
[37]
E. Itakura, C. Kishi, K. Inoue, and N. Mizushima, “Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG,” Molecular Biology of the Cell, vol. 19, no. 12, pp. 5360–5372, 2008.
[38]
K. Matsunaga, T. Saitoh, K. Tabata et al., “Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages,” Nature Cell Biology, vol. 11, no. 4, pp. 385–396, 2009.
[39]
K. Suzuki, T. Kirisako, Y. Kamada, N. Mizushima, T. Noda, and Y. Ohsumi, “The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation,” The EMBO Journal, vol. 20, no. 21, pp. 5971–5981, 2001.
[40]
K. Obara, T. Noda, K. Niimi, and Y. Ohsumi, “Transport of phosphatidylinositol 3-phosphate into the vacuole via autophagic membranes in Saccharomyces cerevisiae,” Genes to Cells, vol. 13, no. 6, pp. 537–547, 2008.
[41]
T. Proikas-Cezanne and H. Robenek, “Freeze-fracture replica immunolabelling reveals human WIPI-1 and WIPI-2 as membrane proteins of autophagosomes,” Journal of Cellular and Molecular Medicine, vol. 15, pp. 2007–2010, 2011.
[42]
C. Burman and N. T. Ktistakis, “Regulation of autophagy by phosphatidylinositol 3-phosphate,” FEBS Letters, vol. 584, no. 7, pp. 1302–1312, 2010.
[43]
S. Kametaka, T. Okano, M. Ohsumi, and Y. Ohsumi, “Apg14p and Apg6/Vps30p form a protein complex essential for autophagy in the yeast, Saccharomyces cerevisiae,” Journal of Biological Chemistry, vol. 273, no. 35, pp. 22284–22291, 1998.
[44]
S. Pattingre, A. Tassa, X. Qu et al., “Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy,” Cell, vol. 122, no. 6, pp. 927–939, 2005.
[45]
Y. Wei, S. Sinha, and B. Levine, “Dual role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation,” Autophagy, vol. 4, no. 7, pp. 949–951, 2008.
[46]
Y. Wei, S. Pattingre, S. Sinha, M. Bassik, and B. Levine, “JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy,” Molecular Cell, vol. 30, no. 6, pp. 678–688, 2008.
[47]
S. Di Bartolomeo, M. Corazzari, F. Nazio et al., “The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy,” The Journal of Cell Biology, vol. 191, no. 1, pp. 155–168, 2010.
[48]
G. M. Fimia, A. Stoykova, A. Romagnoli et al., “Ambra1 regulates autophagy and development of the nervous system,” Nature, vol. 447, no. 7148, pp. 1121–1125, 2007.
[49]
Y. Takahashi, D. Coppola, N. Matsushita et al., “Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis,” Nature Cell Biology, vol. 9, no. 10, pp. 1142–1151, 2007.
[50]
K. Suzuki, Y. Kubota, T. Sekito, and Y. Ohsumi, “Hierarchy of Atg proteins in pre-autophagosomal structure organization,” Genes to Cells, vol. 12, no. 2, pp. 209–218, 2007.
[51]
C. He, H. Song, T. Yorimitsu et al., “Recruitment of Atg9 to the preautophagosomal structure by Atg11 is essential for selective autophagy in budding yeast,” The Journal of Cell Biology, vol. 175, no. 6, pp. 925–935, 2006.
[52]
A. R. J. Young, E. Y. W. Chan, X. W. Hu et al., “Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes,” Journal of Cell Science, vol. 119, no. 18, pp. 3888–3900, 2006.
[53]
A. Orsi, M. Razi, H. C. Dooley et al., “Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy,” Molecular Biology of the Cell, vol. 23, pp. 1860–1873, 2012.
[54]
M. Mari, J. Griffith, E. Rieter, L. Krishnappa, D. J. Klionsky, and F. Reggiori, “An Atg9-containing compartment that functions in the early steps of autophagosome biogenesis,” The Journal of Cell Biology, vol. 190, no. 6, pp. 1005–1022, 2010.
[55]
Y. Ohashi and S. Munro, “Membrane delivery to the yeast autophagosome from the golgi-endosomal system,” Molecular Biology of the Cell, vol. 21, no. 22, pp. 3998–4008, 2010.
[56]
H. Yamamoto, S. Kakuta, T. M. Watanabe et al., “Atg9 vesicles are an important membrane source during early steps of autophagosome formation,” The Journal of Cell Biology, vol. 198, pp. 219–233, 2012.
[57]
F. Reggiori, K. A. Tucker, P. E. Stromhaug, and D. J. Klionsky, “The Atg1-Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure,” Developmental Cell, vol. 6, no. 1, pp. 79–90, 2004.
[58]
A. K. Velikkakath, T. Nishimura, E. Oita, N. Ishihara, and N. Mizushima, “Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets,” Molecular Biology of the Cell, vol. 23, pp. 896–909, 2012.
[59]
K. Obara, T. Sekito, K. Niimi, and Y. Ohsumi, “The Atg18-Atg2 complex is recruited to autophagic membranes via phosphatidylinositol 3-phosphate and exerts an essential function,” Journal of Biological Chemistry, vol. 283, no. 35, pp. 23972–23980, 2008.
[60]
C. Behrends, M. E. Sowa, S. P. Gygi, and J. W. Harper, “Network organization of the human autophagy system,” Nature, vol. 466, no. 7302, pp. 68–76, 2010.
[61]
N. Mizushima, T. Noda, T. Yoshimori et al., “A protein conjugation system essential for autophagy,” Nature, vol. 395, no. 6700, pp. 395–398, 1998.
[62]
T. Shpilka, N. Mizushima, and Z. Elazar, “Ubiquitin-like proteins and autophagy at a glance,” Journal of Cell Science, vol. 125, pp. 2343–2348, 2012.
[63]
I. Tanida, T. Ueno, and E. Kominami, “LC3 conjugation system in mammalian autophagy,” International Journal of Biochemistry and Cell Biology, vol. 36, no. 12, pp. 2503–2518, 2004.
[64]
N. Fujita, T. Itoh, H. Omori, M. Fukuda, T. Noda, and T. Yoshimori, “The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy,” Molecular Biology of the Cell, vol. 19, no. 5, pp. 2092–2100, 2008.
[65]
T. Hanada, N. N. Noda, Y. Satomi et al., “The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy,” Journal of Biological Chemistry, vol. 282, no. 52, pp. 37298–37302, 2007.
[66]
H. Nakatogawa, Y. Ichimura, and Y. Ohsumi, “Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion,” Cell, vol. 130, no. 1, pp. 165–178, 2007.
[67]
H. Weidberg, T. Shpilka, E. Shvets, A. Abada, F. Shimron, and Z. Elazar, “LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis,” Developmental Cell, vol. 20, no. 4, pp. 444–454, 2011.
[68]
U. Nair, A. Jotwani, J. Geng et al., “SNARE proteins are required for macroautophagy,” Cell, vol. 146, pp. 290–302, 2011.
[69]
E. L. Axe, S. A. Walker, M. Manifava et al., “Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum,” The Journal of Cell Biology, vol. 182, no. 4, pp. 685–701, 2008.
[70]
E. Itakura and N. Mizushima, “Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins,” Autophagy, vol. 6, no. 6, pp. 764–776, 2010.
[71]
A. Ropolo, D. Grasso, R. Pardo et al., “The pancreatitis-induced vacuole membrane protein 1 triggers autophagy in mammalian cells,” Journal of Biological Chemistry, vol. 282, no. 51, pp. 37124–37133, 2007.
[72]
K. Suzuki and Y. Ohsumi, “Current knowledge of the pre-autophagosomal structure (PAS),” FEBS Letters, vol. 584, no. 7, pp. 1280–1286, 2010.
[73]
E. Itakura, C. Kishi-Itakura, I. Koyama-Honda, and N. Mizushima, “Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy,” Journal of Cell Science, vol. 125, pp. 1488–1499, 2012.
[74]
S. Kageyama, H. Omori, T. Saitoh et al., “The LC3 recruitment mechanism is separate from Atg9L1-dependent membrane formation in the autophagic response against Salmonella,” Molecular Biology of the Cell, vol. 22, no. 13, pp. 2290–2300, 2011.
[75]
T. Noda, S. Kageyama, N. Fujita, and T. Yoshimori, “Three-axis model for Atg recruitment in autophagy against Salmonella,” International Journal of Cell Biology, vol. 2012, Article ID 389562, 2012.
[76]
M. Mari, S. A. Tooze, and F. Reggiori, “The puzzling origin of the autophagosomal membrane,” F1000 Biology Reports, vol. 3, article 25, 2011.
[77]
F. Reggiori and S. A. Tooze, “The EmERgence of autophagosomes,” Developmental Cell, vol. 17, no. 6, pp. 747–748, 2009.
[78]
S. A. Tooze and T. Yoshimori, “The origin of the autophagosomal membrane,” Nature Cell Biology, vol. 12, no. 9, pp. 831–835, 2010.
[79]
K. Moreau, B. Ravikumar, M. Renna, C. Puri, and D. C. Rubinsztein, “Autophagosome precursor maturation requires homotypic fusion,” Cell, vol. 146, no. 2, pp. 303–317, 2011.
[80]
M. Hayashi-Nishino, N. Fujita, T. Noda, A. Yamaguchi, T. Yoshimori, and A. Yamamoto, “A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation,” Nature Cell Biology, vol. 11, no. 12, pp. 1433–1437, 2009.
[81]
P. Yl？-Anttila, H. Vihinen, E. Jokitalo, and E. L. Eskelinen, “3D tomography reveals connections between the phagophore and endoplasmic reticulum,” Autophagy, vol. 5, no. 8, pp. 1180–1185, 2009.
[82]
T. Noda, N. Fujita, and T. Yoshimori, “The late stages of autophagy: how does the end begin?” Cell Death and Differentiation, vol. 16, no. 7, pp. 984–990, 2009.
[83]
T. Kirisako, M. Baba, N. Ishihara et al., “Formation process of autophagosome is traced with Apg8/Aut7p in yeast,” The Journal of Cell Biology, vol. 147, no. 2, pp. 435–446, 1999.
[84]
U. Nair, W. L. Yen, M. Mari et al., “A role for Atg8-PE deconjugation in autophagosome biogenesis,” Autophagy, vol. 8, no. 5, pp. 780–793, 2012.
[85]
H. Nakatogawa, J. Ishii, E. Asai, and Y. Ohsumi, “Atg4 recycles inappropriately lipidated Atg8 to promote autophagosome biogenesis,” Autophagy, vol. 8, pp. 177–186, 2012.
[86]
E. Cebollero, A. van der Vaart, M. Zhao et al., “Phosphatidylinositol-3-phosphate clearance plays a key role in autophagosome completion,” Current Biology, vol. 22, no. 17, pp. 1545–1553, 2012.
[87]
A. J. Meijer and P. Codogno, “Autophagy: regulation and role in disease,” Critical Reviews in Clinical Laboratory Sciences, vol. 46, no. 4, pp. 210–240, 2009.
[88]
H. I. Mack, B. Zheng, J. Asara, and S. M. Thomas, “AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization,” Autophagy, vol. 8, pp. 1197–1214, 2012.
[89]
J. L. Webber and S. A. Tooze, “Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP,” The EMBO journal, vol. 29, no. 1, pp. 27–40, 2010.
[90]
J. Kim, M. Kundu, B. Viollet, and K. L. Guan, “AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1,” Nature Cell Biology, vol. 13, no. 2, pp. 132–141, 2011.
[91]
L. Shang, S. Chen, F. Du, S. Li, L. Zhao, and X. Wang, “Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 12, pp. 4788–4793, 2011.
[92]
J. S. Stephan, Y. Y. Yeh, V. Ramachandran, S. J. Deminoff, and P. K. Herman, “The Tor and PKA signaling pathways independently target the Atg1/Atg13 protein kinase complex to control autophagy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 40, pp. 17049–17054, 2009.
[93]
M. Delgado, S. Singh, S. De Haro et al., “Autophagy and pattern recognition receptors in innate immunity,” Immunological Reviews, vol. 227, no. 1, pp. 189–202, 2009.
[94]
M. A. Delgado and V. Deretic, “Toll-like receptors in control of immunological autophagy,” Cell Death and Differentiation, vol. 16, no. 7, pp. 976–983, 2009.
[95]
S. Wu and J. Sun, “Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection,” Discovery Medicine, vol. 11, pp. 325–335, 2011.
[96]
Y. Chen and D. J. Klionsky, “The regulation of autophagy—unanswered questions,” Journal of Cell Science, vol. 124, no. 2, pp. 161–170, 2011.
[97]
C. Kraft, M. Peter, and K. Hofmann, “Selective autophagy: ubiquitin-mediated recognition and beyond,” Nature Cell Biology, vol. 12, no. 9, pp. 836–841, 2010.
[98]
T. Johansen and T. Lamark, “Selective autophagy mediated by autophagic adapter proteins,” Autophagy, vol. 7, no. 3, pp. 279–296, 2011.
[99]
P. K. Kim, D. W. Hailey, R. T. Mullen, and J. Lippincott-Schwartz, “Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 52, pp. 20567–20574, 2008.
[100]
A. Orvedahl, R. Sumpter Jr., G. Xiao et al., “Image-based genome-wide siRNA screen identifies selective autophagy factors,” Nature, vol. 480, pp. 113–117, 2011.
[101]
R. O. Watson, P. S. Manzanillo, and J. S. Cox, “Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway,” Cell, vol. 150, pp. 803–815, 2012.
[102]
J. C. Farré, R. Manjithaya, R. D. Mathewson, and S. Subramani, “PpAtg30 tags peroxisomes for turnover by selective autophagy,” Developmental Cell, vol. 14, no. 3, pp. 365–376, 2008.
[103]
T. Kanki, K. Wang, Y. Cao, M. Baba, and D. J. Klionsky, “Atg32 is a mitochondrial protein that confers selectivity during mitophagy,” Developmental Cell, vol. 17, no. 1, pp. 98–109, 2009.
[104]
K. Okamoto, N. Kondo-Okamoto, and Y. Ohsumi, “Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy,” Developmental Cell, vol. 17, no. 1, pp. 87–97, 2009.
[105]
Y. Aoki, T. Kanki, Y. Hirota et al., “Phosphorylation of serine 114 on Atg32 mediates mitophagy,” Molecular Biology of the Cell, vol. 22, pp. 3206–3217, 2011.
[106]
R. Manjithaya, S. Jain, J. C. Farré, and S. Subramani, “A yeast MAPK cascade regulates pexophagy but not other autophagy pathways,” The Journal of Cell Biology, vol. 189, no. 2, pp. 303–310, 2010.
[107]
A. M. Motley, J. M. Nuttall, and E. H. Hettema, “Pex3-anchored Atg36 tags peroxisomes for degradation in Saccharomyces cerevisiae,” The EMBO Journal, vol. 31, pp. 2852–2868, 2012.
[108]
M. A. Lynch-Day and D. J. Klionsky, “The Cvt pathway as a model for selective autophagy,” FEBS Letters, vol. 584, no. 7, pp. 1359–1366, 2010.
[109]
J. M. Duran, C. Anjard, C. Stefan, W. F. Loomis, and V. Malhotra, “Unconventional secretion of Acb1 is mediated by autophagosomes,” The Journal of Cell Biology, vol. 188, no. 4, pp. 527–536, 2010.
[110]
R. Manjithaya, C. Anjard, W. F. Loomis, and S. Subramani, “Unconventional secretion of Pichia pastoris Acb1 is dependent on GRASP protein, peroxisomal functions, and autophagosome formation,” The Journal of Cell Biology, vol. 188, no. 4, pp. 537–546, 2010.
[111]
C. Bruns, J. M. McCaffery, A. J. Curwin, J. M. Duran, and V. Malhotra, “Biogenesis of a novel compartment for autophagosome-mediated unconventional protein secretion,” The Journal of Cell Biology, vol. 195, pp. 979–992, 2011.
[112]
N. Dupont, S. Jiang, M. Pilli, W. Ornatowski, D. Bhattacharya, and V. Deretic, “Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1B,” The EMBO Journal, vol. 30, pp. 4701–4711, 2011.
[113]
R. E. Griffiths, S. Kupzig, N. Cogan et al., “Maturing reticulocytes internalize plasma membrane in glycophorin A-containing vesicles that fuse with autophagosomes before exocytosis,” Blood, vol. 119, pp. 6296–6306, 2012.
[114]
M. P. Taylor and K. Kirkegaard, “Potential subversion of autophagosomal pathway by picornaviruses,” Autophagy, vol. 4, no. 3, pp. 286–289, 2008.
[115]
S. Bernales, K. L. McDonald, and P. Walter, “Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response,” PLoS Biology, vol. 4, no. 12, article e423, 2006.
[116]
V. Deretic and B. Levine, “Autophagy, immunity, and microbial adaptations,” Cell Host and Microbe, vol. 5, no. 6, pp. 527–549, 2009.
[117]
P. Codogno, M. Mehrpour, and T. Proikas-Cezanne, “Canonical and non-canonical autophagy: variations on a common theme of self-eating? Nature reviews,” Molecular Cell Biology, vol. 13, pp. 7–12, 2012.
[118]
T. Proikas-Cezanne and P. Codogno, “Beclin 1 or not Beclin 1,” Autophagy, vol. 7, no. 7, pp. 671–672, 2011.
[119]
Y. Nishida, S. Arakawa, K. Fujitani et al., “Discovery of Atg5/Atg7-independent alternative macroautophagy,” Nature, vol. 461, no. 7264, pp. 654–658, 2009.
[120]
Y. Grishchuk, V. Ginet, A. C. Truttmann, P. G. Clarke, and J. Puyal, “Beclin 1-independent autophagy contributes to apoptosis in cortical neurons,” Autophagy, vol. 7, pp. 1115–1131, 2011.
[121]
M. Mauthe, A. Jacob, S. Freiberger et al., “Resveratrol-mediated autophagy requires WIPI-1-regulated LC3 lipidation in the absence of induced phagophore formation,” Autophagy, vol. 7, pp. 1448–1461, 2011.
[122]
F. Scarlatti, R. Maffei, I. Beau, P. Codogno, and R. Ghidoni, “Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells,” Cell Death and Differentiation, vol. 15, no. 8, pp. 1318–1329, 2008.
[123]
S. Tian, J. Lin, J. Zhou et al., “Beclin 1-independent autophagy induced by a Bcl-XL/Bcl-2 targeting compound, Z18,” Autophagy, vol. 6, no. 8, pp. 1032–1041, 2010.
[124]
J. H. Zhu, C. Horbinski, F. Guo, S. Watkins, Y. Uchiyama, and C. T. Chu, “Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death,” American Journal of Pathology, vol. 170, no. 1, pp. 75–86, 2007.
[125]
P. Gao, C. Bauvy, S. Souquère et al., “The Bcl-2 homology domain 3 mimetic gossypol induces both beclin 1-dependent and beclin 1-independent cytoprotective autophagy in cancer cells,” Journal of Biological Chemistry, vol. 285, no. 33, pp. 25570–25581, 2010.
[126]
D. M. Smith, S. Patel, F. Raffoul, E. Haller, G. B. Mills, and M. Nanjundan, “Arsenic trioxide induces a beclin-1-independent autophagic pathway via modulation of SnoN/SkiL expression in ovarian carcinoma cells,” Cell Death and Differentiation, vol. 17, no. 12, pp. 1867–1881, 2010.
[127]
R. Bernasconi and M. Molinari, “ERAD and ERAD tuning: disposal of cargo and of ERAD regulators from the mammalian ER,” Current Opinion in Cell Biology, vol. 23, no. 2, pp. 176–183, 2011.
[128]
T. Calì, C. Galli, S. Olivari, and M. Molinari, “Segregation and rapid turnover of EDEM1 by an autophagy-like mechanism modulates standard ERAD and folding activities,” Biochemical and Biophysical Research Communications, vol. 371, no. 3, pp. 405–410, 2008.
[129]
T. Calì, O. Vanoni, and M. Molinari, “The endoplasmic reticulum crossroads for newly synthesized polypeptide chains,” Progress in Molecular Biology and Translational Science, vol. 83, pp. 135–179, 2008.
[130]
R. Bernasconi, C. Galli, J. Noack et al., “Role of the SEL1L:LC3-I complex as an ERAD tuning receptor in the mammalian ER,” Molecular Cell, vol. 46, pp. 809–819, 2012.
[131]
F. Reggiori, I. Monastyrska, M. H. Verheije et al., “Coronaviruses hijack the LC3-I-positive EDEMosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication,” Cell Host and Microbe, vol. 7, no. 6, pp. 500–508, 2010.
[132]
I. Monastyrska, E. Rieter, D. J. Klionsky, and F. Reggiori, “Multiple roles of the cytoskeleton in autophagy,” Biological Reviews, vol. 84, no. 3, pp. 431–448, 2009.
[133]
Z. Zhao, L. B. Thackray, B. C. Miller et al., “Coronavirus replication does not require the autophagy gene ATG5,” Autophagy, vol. 3, no. 6, pp. 581–585, 2007.
[134]
I. Monastyrska, M. Ulasli, P. J. Rottier, J. L. Guan, F. Reggiori, and C. A. de Haan, “An autophagy-independent role for LC3 in equine arteritis virus replication,” Autophagy. In press.
[135]
H. M. Al-Younes, M. A. Al-Zeer, H. Khalil et al., “Autophagy-independent function of MAP-LC3 during intracellular propagation of Chlamydia trachomatis,” Autophagy, vol. 7, no. 8, pp. 814–828, 2011.
[136]
N. Pachikara, H. Zhang, Z. Pan, S. Jin, and H. Fan, “Productive Chlamydia trachomatis lymphogranuloma venereum 434 infection in cells with augmented or inactivated autophagic activities,” FEMS Microbiology Letters, vol. 292, no. 2, pp. 240–249, 2009.
[137]
J. Celli, “Surviving inside a macrophage: the many ways of Brucella,” Research in Microbiology, vol. 157, no. 2, pp. 93–98, 2006.
[138]
T. Starr, R. Child, T. D. Wehrly et al., “Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle,” Cell Host and Microbe, vol. 11, pp. 33–45, 2012.
[139]
F. P. Coxon and A. Taylor, “Vesicular trafficking in osteoclasts,” Seminars in Cell and Developmental Biology, vol. 19, no. 5, pp. 424–433, 2008.
[140]
C. J. DeSelm, B. C. Miller, W. Zou et al., “Autophagy proteins regulate the secretory component of osteoclastic bone resorption,” Developmental Cell, vol. 21, pp. 966–974, 2011.
[141]
O. Florey, S. E. Kim, C. P. Sandoval, C. M. Haynes, and M. Overholtzer, “Autophagy machinery mediates macroendocytic processing and entotic cell death by targeting single membranes,” Nature Cell Biology, vol. 13, pp. 1335–1343, 2011.
[142]
J. Martinez, J. Almendinger, A. Oberst et al., “Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, pp. 17396–17401, 2011.
[143]
M. A. Sanjuan, C. P. Dillon, S. W. G. Tait et al., “Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis,” Nature, vol. 450, no. 7173, pp. 1253–1257, 2007.
[144]
W. Li, W. Zou, Y. Yang et al., “Autophagy genes function sequentially to promote apoptotic cell corpse degradation in the engulfing cell,” The Journal of Cell Biology, vol. 197, pp. 27–35, 2012.
[145]
M. Ponpuak, A. S. Davis, E. A. Roberts et al., “Delivery of cytosolic components by autophagic adaptor protein p62 endows autophagosomes with unique antimicrobial properties,” Immunity, vol. 32, no. 3, pp. 329–341, 2010.
[146]
S. Hwang, N. S. Maloney, M. W. Bruinsma et al., “Nondegradative role of Atg5-Atg12/ Atg16L1 autophagy protein complex in antiviral activity of interferon gamma,” Cell Host and Microbe, vol. 11, pp. 397–409, 2012.
