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Binding of the Atg1/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy.

ABSTRACT: Autophagy is an intracellular trafficking pathway sequestering cytoplasm and delivering excess and damaged cargo to the vacuole for degradation. The Atg1/ULK1 kinase is an essential component of the core autophagy machinery possibly activated by binding to Atg13 upon starvation. Indeed, we found that Atg13 directly binds Atg1, and specific Atg13 mutations abolishing this interaction interfere with Atg1 function in vivo. Surprisingly, Atg13 binding to Atg1 is constitutive and not altered by nutrient conditions or treatment with the Target of rapamycin complex 1 (TORC1)-inhibitor rapamycin. We identify Atg8 as a novel regulator of Atg1/ULK1, which directly binds Atg1/ULK1 in a LC3-interaction region (LIR)-dependent manner. Molecular analysis revealed that Atg13 and Atg8 cooperate at different steps to regulate Atg1 function. Atg8 targets Atg1/ULK1 to autophagosomes, where it may promote autophagosome maturation and/or fusion with vacuoles/lysosomes. Moreover, Atg8 binding triggers vacuolar degradation of the Atg1-Atg13 complex in yeast, thereby coupling Atg1 activity to autophagic flux. Together, these findings define a conserved step in autophagy regulation in yeast and mammals and expand the known functions of LIR-dependent Atg8 targets to include spatial regulation of the Atg1/ULK1 kinase.

SUBMITTER: Kraft C

PROVIDER: S-EPMC3442273 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Binding of the Atg1/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy.

Kraft Claudine C Kijanska Monika M Kalie Eyal E Siergiejuk Edyta E Lee Sung Sik SS Semplicio Giuseppe G Stoffel Ingrid I Brezovich Andrea A Verma Mayanka M Hansmann Isabella I Ammerer Gustav G Hofmann Kay K Tooze Sharon S Peter Matthias M

The EMBO journal 20120810 18

Autophagy is an intracellular trafficking pathway sequestering cytoplasm and delivering excess and damaged cargo to the vacuole for degradation. The Atg1/ULK1 kinase is an essential component of the core autophagy machinery possibly activated by binding to Atg13 upon starvation. Indeed, we found that Atg13 directly binds Atg1, and specific Atg13 mutations abolishing this interaction interfere with Atg1 function in vivo. Surprisingly, Atg13 binding to Atg1 is constitutive and not altered by nutri ...[more]

PMID: 22885598

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Project description:ULK1 (unc-51 like autophagy activating kinase 1) is a core component at multiple steps of canonical macroautophagy/autophagy. The activity of ULK1 is tightly regulated by several post-translational modifications, including ubiquitination, yet the deubiquitinase (DUB) responsible for its reversible deubiquitination has not been described. Here, we identified USP1 (ubiquitin specific peptidase 1) as a key player in the modulation of ULK1 K63-linked deubiquitination. Moreover, both USP1 depletion and its chemical inhibition by pimozide are coupled to a reduction of ULK1 in Triton X-100 soluble cellular lysates, and its compartmentalization to a fraction that can be solubilized in 5 M urea. In USP1-depleted cells this fraction is also enriched in SQSTM1 (sequestosome 1), the aggresome marker HDAC6 (histone deacetylase 6), and the prototype of USP1 targets FANCD2 (FA complementation group D2). Consistently, in USP1-depleted and pimozide-treated cells, ULK1 forms protein aggregates enriched in SQSTM1, as detected by both immummunofluorescence and co-immunoprecipitation studies. Notably, depletion of USP1 inhibits canonical autophagic flux and promotes an alternative route leading to lysosomal-mediated degradation of SQSTM1. Our findings reveal a novel function of the USP1-ULK1 axis as a modulator of the switch between canonical and unconventional autophagy. Further, we provide the first evidence supporting the existence of a subset of breast tumors co-expressing ULK1 and MAP1LC3B (microtubule associated protein 1 light chain 3 beta) proteins. Because the USP1 inhibitor pimozide affects breast cancer cell growth, targeting USP1 in those tumors relying on autophagy for growth might prove to be a convenient therapeutic strategy. Abbreviations: ATG13: autophagy related 13; BECN1: beclin 1; BZ: bortezomib; CAPN1: calpain 1; DUB: deubiquitinase; FANCI: FA complementation group I; FANCD2: FA complementation group D2; FZR1: fizzy and cell division cycle 20 related 1; HDAC6: histone deacetylase 6; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; PMZ: pimozide; SH3GLB1: SH3 domain containing GRB2 like, endophilin B1; SQSTM1: sequestosome 1; TRAF6: TNF receptor associated factor 6; ULK1: unc-51 like autophagy activating kinase 1; USP1: ubiquitin specific peptidase 1; WDR48: WD repeat domain 48.

Dataset Information

Binding of the Atg1/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy.

Publications

Binding of the Atg1/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy.

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