Journal Article

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

Kijanska, Monika, Kraft, Claudine, Stoffel, Ingrid, Ammerer, Gustav, Hofmann, Kay, Tooze, Sharon, Semplicio, Giuseppe, Peter, Matthias, Siergiejuk, Edyta, Brezovich, Andrea, Verma, Mayanka, Hansmann, Isabella, Kalie, Eyal, Lee, Sung Sik

2012

Overview

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. The Atg1/ULK1 kinase is an essential component of the core autophagy machinery and needs to be regulated in response to nutrient availability. A novel conserved mechanism to balance autophagic flux during nutrient depletion involves Atg8‐dependent targeting of the Atg1–Atg13 complex to autophagy‐mediated degradation.

• Publisher: John Wiley & Sons, Ltd,Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: Adaptor Proteins, Signal Transducing - metabolism / Atg1-ULK1 kinase / Atg8 / Autophagy / Autophagy-Related Protein 8 Family / Autophagy-Related Protein-1 Homolog / Autophagy-Related Proteins / Base Sequence / Cellular biology / Cvt pathway / EMBO07 / EMBO37 / Gene Expression Regulation / HEK293 Cells / Humans / Intracellular Signaling Peptides and Proteins - metabolism / Kinases / LIR motif / Mammals / Mechanistic Target of Rapamycin Complex 1 / Microfilament Proteins - metabolism / Models, Genetic / Molecular biology / Molecular Sequence Data / Multiprotein Complexes / Mutation / Nutrients / Protein Binding / Protein Isoforms / Protein Serine-Threonine Kinases - metabolism / Proteins / Proteins - metabolism / Sequence Homology, Nucleic Acid / TOR Serine-Threonine Kinases / Vacuoles - metabolism / Yeast / Yeasts