Autophagy and the nutritional signaling pathway

Abstract

During their growth and development, animals adapt to tremendous changes in order to survive. These include responses to both environmental and physiological changes and autophagy is one of most important adaptive and regulatory mechanisms. Autophagy is defined as an autolytic process to clear damaged cellular organelles and recycle the nutrients via lysosomic degradation. The process of autophagy responds to special conditions such as nutrient withdrawal. Once autophagy is induced, phagophores form and then elongate and curve to form autophagosomes. Autophagosomes then engulf cargo, fuse with endosomes, and finally fuse with lysosomes for maturation. During the initiation process, the ATG1/ULK1 (unc-51-like kinase 1) and VPS34 (which encodes a class III phosphatidylinositol (PtdIns) 3-kinase) complexes are critical in recruitment and assembly of other complexes required for autophagy. The process of autophagy is regulated by autophagy related genes (ATGs). Amino acid and energy starvation mediate autophagy by activating mTORC1 (mammalian target of rapamycin) and AMP-activated protein kinase (AMPK). AMPK is the energy status sensor, the core nutrient signaling component and the metabolic kinase of cells. This review mainly focuses on the mechanism of autophagy regulated by nutrient signaling especially for the two important complexes, ULK1 and VPS34.

Keywords

Autophagy / ULK1 complex / VPS34 complex / AMPK / mTOR / nutrient signaling

References

[1] Xie Z, Klionsky D J. Autophagosome formation: core machinery and adaptations. Nature Cell Biology, 2007, 9(10): 1102–1109

[2] Mizushima N, Levine B, Cuervo A M, Klionsky D J. Autophagy fights disease through cellular self-digestion. Nature, 2008, 451(7182): 1069–1075

[3] Renna M, Bento C F, Ghislat G, Puri C, Ashkenazi A, Vicinanza M, Menzies F M, Rubinsztein D C. Mammalian autophagy-how does it work? Annual Review of Biochemistry, 2016 (first published online)

[4] Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. Journal of Cell Biology, 2000, 150(6): 1507–1513

[5] Kim J, Kim Y C, Fang C, Russell R C, Kim J H, Fan W, Liu R, Zhong Q, Guan K L. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell, 2013, 152(1–2): 290–303

[6] Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N. The role of autophagy during the early neonatal starvation period. Nature, 2004, 432(7020): 1032–1036

[7] Zhang S, Li X, Li L, Yan X. Autophagy up-regulation by early weaning in the liver, spleen and skeletal muscle of piglets. British Journal of Nutrition, 2011, 106(2): 213–217

[8] Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N. The role of autophagy during the early neonatal starvation period. Nature, 2004, 432(7020): 1032–1036

[9] Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, Kominami E, Tanaka K, Chiba T. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. Journal of Cell Biology, 2005, 169(3): 425–434

[10] Rabinowitz J D, White E. Autophagy and metabolism. Science, 2010, 330(6009): 1344–1348

[11] Deretic V, Levine B. Autophagy, immunity, and microbial adaptations. Cell Host & Microbe, 2009, 5(6): 527–549

[12] Levine B, Mizushima N, Virgin H W. Autophagy in immunity and inflammation. Nature, 2011, 469(7330): 323–335

[13] Jia K, Thomas C, Akbar M, Sun Q, Adams-Huet B, Gilpin C, Levine B. Autophagy genes protect against Salmonella typhimurium infection and mediate insulin signaling-regulated pathogen resistance. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(34): 14564–14569

[14] Kuballa P, Huett A, Rioux J D, Daly M J, Xavier R J. Impaired autophagy of an intracellular pathogen induced by a Crohn’s disease associated ATG16L1 variant. PLoS ONE, 2008, 3(10): e3391

[15] Wild P, Farhan H, McEwan D G, Wagner S, Rogov V V, Brady N R, Richter B, Korac J, Waidmann O, Choudhary C, Dötsch V, Bumann D, Dikic I. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science, 2011, 333(6039): 228–233

[16] Benjamin J L, Sumpter R Jr, Levine B, Hooper L V. Intestinal epithelial autophagy is essential for host defense against invasive bacteria. Cell Host & Microbe, 2013, 13(6): 723–734

[17] Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein D C. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nature Cell Biology, 2010, 12(8): 747–757

[18] Yamamoto A, Masaki R, Tashiro Y. Characterization of the isolation membranes and the limiting membranes of autophagosomes in rat hepatocytes by lectin cytochemistry. Journal of Histochemistry and Cytochemistry, 1990, 38(4): 573–580

[19] Suzuki K, Kirisako T, Kamada Y, Mizushima N, Noda T, Ohsumi Y. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO Journal, 2001, 20(21): 5971–5981

[20] Itakura E, Mizushima N. Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy, 2010, 6(6): 764–776

[21] Simonsen A, Stenmark H. Self-eating from an ER-associated cup. Journal of Cell Biology, 2008, 182(4): 621–622

[22] Noda T, Kim J, Huang W, Baba M, Tokunaga C, Ohsumi Y, Klionsky D J. Apg9p/Cvt7p is an integral membrane protein required for transport vesicle formation in the Cvt and autophagy pathways. Journal of Cell Biology, 2000, 148(3): 465–480

[23] Reggiori F, Shintani T, Chong H, Nair U, Klionsky D J. Atg9 cycles between mitochondria and the pre-autophagosomal structure in yeasts. Autophagy, 2005, 1(2): 101–109

[24] Guan J, Stromhaug P E, George M D, Habibzadegah-Tari P, Bevan A, Dunn W A Jr, Klionsky D J. Cvt18/Gsa12 is required for cytoplasm-to-vacuole transport, pexophagy, and autophagy in Saccharomyces cerevisiae and Pichia pastoris. Molecular Biology of the Cell, 2001, 12(12): 3821–3838

[25] Matsuura A, Tsukada M, Wada Y, Ohsumi Y. Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene, 1997, 192(2): 245–250

[26] Kirisako T, Ichimura Y, Okada H, Kabeya Y, Mizushima N, Yoshimori T, Ohsumi M, Takao T, Noda T, Ohsumi Y. The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway. Journal of Cell Biology, 2000, 151(2): 263–276

[27] Mizushima N, Kuma A, Kobayashi Y, Yamamoto A, Matsubae M, Takao T, Natsume T, Ohsumi Y, Yoshimori T. Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. Journal of Cell Science, 2003, 116(9): 1679–1688

[28] Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO Journal, 2000, 19(21): 5720–5728

[29] Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, Tokuhisa T, Ohsumi Y, Yoshimori T. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. Journal of Cell Biology, 2001, 152(4): 657–668

[30] Kim J, Kamada Y, Stromhaug P E, Guan J, Hefner-Gravink A, Baba M, Scott S V, Ohsumi Y, Dunn W A Jr, Klionsky D J. Cvt9/Gsa9 functions in sequestering selective cytosolic cargo destined for the vacuole. Journal of Cell Biology, 2001, 153(2): 381–396

[31] Takáts S, Nagy P, Varga Á, Pircs K, Kárpáti M, Varga K, Kovács A L, Hegedűs K, Juhász G. Autophagosomal Syntaxin17-dependent lysosomal degradation maintains neuronal function in Drosophila. Journal of Cell Biology, 2013, 201(4): 531–539

[32] Atlashkin V, Kreykenbohm V, Eskelinen E L, Wenzel D, Fayyazi A, Fischer von Mollard G. Deletion of the SNARE vti1b in mice results in the loss of a single SNARE partner, syntaxin 8. Molecular and Cellular Biology, 2003, 23(15): 5198–5207

[33] Fader C M, Sánchez D G, Mestre M B, Colombo M I. TI-VAMP/VAMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. Biochimica et Biophysica Acta, 2009, 1793(12): 1901–1916

[34] Itakura E, Kishi-Itakura C, Mizushima N. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell, 2012, 151(6): 1256–1269

[35] Diao J, Liu R, Rong Y, Zhao M, Zhang J, Lai Y, Zhou Q, Wilz L M, Li J, Vivona S, Pfuetzner R A, Brunger A T, Zhong Q. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature, 2015, 520(7548): 563–566

[36] Razi M, Chan E Y, Tooze S A. Early endosomes and endosomal coatomer are required for autophagy. Journal of Cell Biology, 2009, 185(2): 305–321

[37] Lee J A, Beigneux A, Ahmad S T, Young S G, Gao F B. ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Current Biology, 2007, 17(18): 1561–1567

[38] Nickerson D P, Brett C L, Merz A J. Vps-C complexes: gatekeepers of endolysosomal traffic. Current Opinion in Cell Biology, 2009, 21(4): 543–551

[39] Eskelinen E L, Illert A L, Tanaka Y, Schwarzmann G, Blanz J, von Figura K, Saftig P. Role of LAMP-2 in lysosome biogenesis and autophagy. Molecular Biology of the Cell, 2002, 13(9): 3355– 3368

[40] Hyttinen J M T, Niittykoski M, Salminen A, Kaarniranta K. Maturation of autophagosomes and endosomes: a key role for Rab7. Biochimica et Biophysica Acta, 2013, 1833(3): 503–510

[41] Liang C, Lee J S, Inn K S, Gack M U, Li Q, Roberts E A, Vergne I, Deretic V, Feng P, Akawa C, Jung J U. Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nature Cell Biology, 2008, 10(7): 776–787

[42] Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama-Noda K, Ichimura T, Isobe T, Akira S, Noda T, Yoshimori T. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nature Cell Biology, 2009, 11(4): 385–396

[43] Chen D, Fan W, Lu Y, Ding X, Chen S, Zhong Q. A mammalian autophagosome maturation mechanism mediated by TECPR1 and the Atg12-Atg5 conjugate. Molecular Cell, 2012, 45(5): 629–641

[44] Jewell J L, Russell R C, Guan K L. Amino acid signalling upstream of mTOR. Nature Reviews Molecular Cell Biology, 2013, 14(3): 133–139

[45] Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, Dai N. Amino acid regulation of TOR complex 1. American Journal of Physiology: Endocrinology and Metabolism, 2009, 296(4): 592–602

[46] Oshiro N, Takahashi R, Yoshino K I, Tanimura K, Nakashima A, Eguchi S, Miyamoto T, Hara K, Takehana K, Avruch J, Kikkawa U, Yonezawa K. The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. Journal of Biological Chemistry, 2007, 282(28): 20329–20339

[47] Laplante M, Sabatini D M. mTOR signaling in growth control and disease. Cell, 2012, 149(2): 274–293

[48] Hardie D G. AMP-activated protein kinase—an energy sensor that regulates all aspects of cell function. Genes & Development, 2011, 25(18): 1895–1908

[49] Habets D D, Coumans W A, El Hasnaoui M, Zarrinpashneh E, Bertrand L, Viollet B, Kiens B, Jensen T E, Richter E A, Bonen A, Glatz J F. Crucial role for LKB1 to AMPKa2 axis in the regulation of CD36-mediated long-chain fatty acid uptake into cardiomyocytes. Biochimica et Biophysica Acta, 2009, 1791(3): 212–219

[50] Winder W W, Holmes B F, Rubink D S, Jensen E B, Chen M, Holloszy J O. Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. Journal of Applied Physiology, 2000, 88(6): 2219–2226

[51] Cantó C, Gerhart-Hines Z, Feige J N, Lagouge M, Noriega L, Milne J C, Elliott P J, Puigserver P, Auwerx J. AMPK regulates energy expenditure by modulating NAD⁺ metabolism and SIRT1 activity. Nature, 2009, 458(7241): 1056–1060

[52] Ganley I G, Lam D H, Wang J, Ding X, Chen S, Jiang X. ULK1–ATG13–FIP200 complex mediates mTOR signaling and is essential for autophagy. Journal of Biological Chemistry, 2009, 284(18): 12297–12305

[53] Papinski D, Kraft C. Regulation of autophagy by signaling through the Atg1/ULK1 complex. Journal of Molecular Biology, 2016, 428(9): 1725–1741

[54] Ktistakis N T, Tooze S A. Digesting the expanding mechanisms of autophagy. Trends in Cell Biology, 2016, (first published online)

[55] Reggiori F, Tucker K A, Stromhaug P E, Klionsky D J. The Atg1-Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure. Developmental Cell, 2004, 6(1): 79–90

[56] Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. Journal of Cell Biology, 2000, 150(6): 1507–1513

[57] Chan E Y, Longatti A, McKnight N C, Tooze S A. Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Molecular and Cellular Biology, 2009, 29(1): 157–171

[58] Noda N N, Mizushima N. Atg101: not just an accessory subunit in the autophagy-initiation complex. Cell Structure and Function, 2016, 41(1): 13–20

[59] Mercer C A, Kaliappan A, Dennis P B. A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy, 2009, 5(5): 649–662

[60] Hara T, Takamura A, Kishi C, Iemura S I, Natsume T, Guan J L, Mizushima N. FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. Journal of Cell Biology, 2008, 181(3): 497–510

[61] Mizushima N. The role of the Atg1/ULK1 complex in autophagy regulation. Current Opinion in Cell Biology, 2010, 22(2): 132–139

[62] Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S I, Natsume T, Takehana K, Yamada N, Guan J L, Oshiro N, Mizushima N. Nutrient-dependent mTORC1 association with the ULK1-Atg13–FIP200 complex required for autophagy. Molecular Biology of the Cell, 2009, 20(7): 1981–1991

[63] Jung C H, Ro S H, Cao J, Otto N M, Kim D H. mTOR regulation of autophagy. FEBS Letters, 2010, 584(7): 1287–1295

[64] Shintani T, Klionsky D J. Autophagy in health and disease: a double-edged sword. Science, 2004, 306(5698): 990–995

[65] Kim J, Kundu M, Viollet B, Guan K L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biology, 2011, 13(2): 132–141

[66] Hardie D G. AMP-activated protein kinase-an energy sensor that regulates all aspects of cell function. Genes & Development, 2011, 25(18): 1895–1908

[67] Nazio F, Strappazzon F, Antonioli M, Bielli P, Cianfanelli V, Bordi M, Gretzmeier C, Dengjel J, Piacentini M, Fimia G M, Cecconi F. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nature Cell Biology, 2013, 15(4): 406–416

[68] Liang J, Shao S H, Xu Z X, Hennessy B, Ding Z, Larrea M, Kondo S, Dumont D J, Gutterman J U, Walker C L, Slingerland J M, Mills G B. The energy sensing LKB1-AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis. Nature Cell Biology, 2007, 9(2): 218–224

[69] Löffler A S, Alers S, Dieterle A M, Keppeler H, Franz-Wachtel M, Kundu M, Campbell D G, Wesselborg S, Alessi D R, Stork B. Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy, 2011, 7(7): 696–706

[70] Obara K, Ohsumi Y. PtdIns 3-kinase orchestrates autophagosome formation in yeast. Journal of Lipids, 2011, 2011: 498768

[71] Kametaka S, Okano T, Ohsumi M, Ohsumi Y. Apg14p and Apg6/Vps30p form a protein complex essential for autophagy in the yeast, Saccharomyces cerevisiae. Journal of Biological Chemistry, 1998, 273(35): 22284–22291

[72] Obara K, Sekito T, Ohsumi Y. Assortment of phosphatidylinositol 3-kinase complexes-Atg14p directs association of complex I to the pre-autophagosomal structure in Saccharomyces cerevisiae. Molecular Biology of the Cell, 2006, 17(4): 1527–1539

[73] Chen J, Li Y, Tian Y, Huang C, Li D, Zhong Q, Ma X. Interaction between microbes and host intestinal health: modulation by dietary nutrients and gut-brain-endocrine-immune axis. Current Protein & Peptide Science, 2015, 16(7): 572–603

[74] Fan P, Li L, Rezaei A, Eslamfam S, Che D, Ma X. Metabolites of dietary protein and peptides by intestinal microbes and their impacts on gut. Current Protein & Peptide Science, 2015, 16(7): 646–654

[75] Ropolo A, Grasso D, Pardo R, Sacchetti M L, Archange C, Re A L, Seux M, Nowak J, Gonzalez C D, Iovanna J L, Vaccaro M I. The pancreatitis-induced vacuole membrane protein 1 triggers autophagy in mammalian cells. Journal of Biological Chemistry, 2007, 282(51): 37124–37133

[76] Fimia G M, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R, Corazzari M, Fuoco C, Ucar A, Schwartz P, Gruss P. Ambra1 regulates autophagy and development of the nervous system. Nature, 2007, 447(7148): 1121–1125

[77] Takahashi Y, Coppola D, Matsushita N, Cualing H D, Sun M, Sato Y, Liang C, Jung J U, Cheng J Q, Mul J J, Pledger W J, Wang H G. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nature Cell Biology, 2007, 9(10): 1142–1151

[78] Zhong Y, Wang Q, Li X, Yan Y, Backer J M, Chait B T, Heintz N, Yue Z. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nature Cell Biology, 2009, 11(4): 468–476

[79] Yuan H, Russell R C, Guan K L. Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy. Autophagy, 2013, 9(12): 1983–1995

[80] Tang Y, Tan B, Xiong X, Li F, Ren W, Kong X, Qiu W, Hardwidge P R, Yin Y. Methionine deficiency reduces autophagy and accelerates death in intestinal epithelial cells infected with enterotoxigenic Escherichia coli. Amino Acids, 2015, 47(10): 2199–2204

[81] Chen R, Wang Q, Song S, Liu F, He B, Gao X. Protective role of autophagy in methionine–choline deficient diet-induced advanced nonalcoholic steatohepatitis in mice. European Journal of Pharmacology, 2016, 5(770): 126–133

[82] Wang S, Tsun Z Y, Wolfson R L, Shen K, Wyant G A, Plovanich M E, Yuan E D, Jones T D, Chantranupong L, Comb W, Wang T, Bar-Peled L, Zoncu R, Straub C, Kim C, Park J, Sabatini B L, Sabatini D M. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science, 2015, 347(6218): 188–194

[83] Munson M J, Allen G F, Toth R, Campbell D G, Lucocq J M, Ganley I G. mTOR activates the VPS34-UVRAG complex to regulate autolysosomal tubulation and cell survival. EMBO Journal, 2015, 34(17): 2272–2290

[84] Ma X, Chen J, Tian Y. Pregnane X receptor as the “sensor and effector” in regulating epigenome. Journal of Cellular Physiology, 2015, 230(4): 752–757

Acknowledgements

The financial support from the China Scholarship Council, the National Basic Research Program of China (2013CB117301), the National Natural Science Foundation of China (31272448, 31472101, 31420103908, and 31528018), the 111 Project (B16044), Beijing Nova Program (xx2013055), Education Foundation of China Agricultural University “Dabeinong Education Fund” (1041-2415001), and National Department Public Benefit Research Foundation (201403047) are gratefully acknowledged

Compliance with ethics guidelines

Long He, Shabnam Eslamfam, Xi Ma, and Defa Li declare that they have no conflicts of interest or financial conflicts to disclose.

This article is a review and does not contain any studies with human or animal subjects performed by any of the authors.

RIGHTS & PERMISSIONS

The Author(s) 2016. Published by Higher Education Press. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0)