title: 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.
authors.affiliation: Institute of Biochemistry, ETH Zürich, Switzerland. claudine.kraft@univie.ac.at
authors.forename: Claudine
authors.initials: C
authors.lastname: Kraft
authors.forename: Monika
authors.initials: M
authors.lastname: Kijanska
authors.forename: Eyal
authors.initials: E
authors.lastname: Kalie
authors.forename: Edyta
authors.initials: E
authors.lastname: Siergiejuk
authors.forename: Sung Sik
authors.initials: SS
authors.lastname: Lee
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Semplicio
authors.forename: Ingrid
authors.initials: I
authors.lastname: Stoffel
authors.forename: Andrea
authors.initials: A
authors.lastname: Brezovich
authors.forename: Mayanka
authors.initials: M
authors.lastname: Verma
authors.forename: Isabella
authors.initials: I
authors.lastname: Hansmann
authors.forename: Gustav
authors.initials: G
authors.lastname: Ammerer
authors.forename: Kay
authors.initials: K
authors.lastname: Hofmann
authors.forename: Sharon
authors.initials: S
authors.lastname: Tooze
authors.forename: Matthias
authors.initials: M
authors.lastname: Peter
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001343:Autophagy; D000071190:Autophagy-Related Protein 8 Family; D000071189:Autophagy-Related Protein-1 Homolog; D000071183:Autophagy-Related Proteins; D001483:Base Sequence; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008840:Microfilament Proteins / Q000378:metabolism*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009154:Mutation; D011485:Protein Binding; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D058570:TOR Serine-Threonine Kinases; D014617:Vacuoles / Q000378:metabolism
chemical_list: C534291:ATG13 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000071190:Autophagy-Related Protein 8 Family; D000071183:Autophagy-Related Proteins; C498698:GABARAPL2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D046912:Multiprotein Complexes; D020033:Protein Isoforms; D011506:Proteins; D000071189:Autophagy-Related Protein-1 Homolog; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human