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Review
. 2015;11(1):28-45.
doi: 10.4161/15548627.2014.984267.

Posttranslational modification of autophagy-related proteins in macroautophagy

Yangchun Xie  1 , Rui Kang, Xiaofang Sun, Meizuo Zhong, Jin Huang, Daniel J Klionsky, Daolin Tang
Affiliations
Review

Posttranslational modification of autophagy-related proteins in macroautophagy

Yangchun Xie et al. Autophagy. 2015.

Abstract

Macroautophagy is an intracellular catabolic process involved in the formation of multiple membrane structures ranging from phagophores to autophagosomes and autolysosomes. Dysfunction of macroautophagy is implicated in both physiological and pathological conditions. To date, 38 autophagy-related (ATG) genes have been identified as controlling these complicated membrane dynamics during macroautophagy in yeast; approximately half of these genes are clearly conserved up to human, and there are additional genes whose products function in autophagy in higher eukaryotes that are not found in yeast. The function of the ATG proteins, in particular their ability to interact with a number of macroautophagic regulators, is modulated by posttranslational modifications (PTMs) such as phosphorylation, glycosylation, ubiquitination, acetylation, lipidation, and proteolysis. In this review, we summarize our current knowledge of the role of ATG protein PTMs and their functional relevance in macroautophagy. Unraveling how these PTMs regulate ATG protein function during macroautophagy will not only reveal fundamental mechanistic insights into the regulatory process, but also provide new therapeutic targets for the treatment of autophagy-associated diseases.

Keywords: AMPK, AMP-activated protein kinase; ATG, autophagy-related; MTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; PTM, posttranslational modification; Ub, ubiquitin; Ubl, ubiquitin like; autophagy; autophagy-related proteins; posttranslational modification.

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Figures

Figure 1.
Figure 1.
Overview of the autophagy process. Autophagy is a lysosome-mediated degradation and recycling pathway that involves the formation of multiple membrane structures ranging from phagophores to autophagosomes and autolysosomes.
Figure 2.
Figure 2.
Regulation of Atg/ATG proteins by phosphorylation. In yeast, the initiation of autophagy involves the inhibition of TORC1- and PKA-mediated phosphorylation of Atg1 and Atg13 under starvation conditions. Atg1 is then activated via autophosphorylation, which is responsible for Atg9 localization to the phagophore assembly site. In addition, phosphorylation of Atg29 stimulates autophagy by activating the Atg17-Atg31-Atg29 complex, which is required for subsequent interaction with Atg11. In mammalian cells, phosphorylation of ULK1 and BECN1 by the indicated kinases has dual roles in the regulation of the autophagic response. Phosphorylation of LC3 and ATG5 by PRKAC and MAPK14, respectively, inhibits autophagy. In addition, ULK1- and ATG101-mediated ATG13 phosphorylation promotes selective autophagy.
Figure 3.
Figure 3.
Regulation of ATG proteins by ubiquitination. (A) Two Ubl conjugation systems in mammalian cells. (B) Ubiquitination or deubiquitination of BECN1 and ULK1 regulate the autophagic response.
Figure 4.
Figure 4.
Regulation of Atg/ATG proteins by acetylation. In yeast, acetylation of Atg3 by Esa1 increases autophagy, whereas deacetylation of Atg3 by Rpd3 decreases autophagy. In mammalian cells, acetylation of ATGs (ATG5, ATG7, ATG8, and ATG12) by EP300 decreases autophagy, whereas deacetylation of these ATGs by SIRT1 increases autophagy. In addition, KAT5-mediated ULK1 acetylation promotes autophagy.
Figure 5.
Figure 5.
Regulation of ATG proteins by proteolysis. CAPN/calpain and CASP can inhibit autophagy by degrading or cleaving ATGs such as ATG3, ATG5, ATG16L1, and BECN1. In contrast, CASP-mediated ATG4D cleavage promotes autophagy. In addition, CTSE/cathepsin E and the 20S proteasome are involved in the degradation of the phagophore and autophagosome membrane component LC3-II.
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