Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination.
Autophagy, a cellular self-eating mechanism, is important for maintaining cell survival and tissue homeostasis in various stressed conditions. Although the molecular mechanism of autophagy induction has been well studied, how cells terminate autophagy process remains elusive. Here, we show that ULK1, a serine/threonine kinase critical for autophagy initiation, is a ... substrate of the Cul3-KLHL20 ubiquitin ligase. Upon autophagy induction, ULK1 autophosphorylation facilitates its recruitment to KLHL20 for ubiquitination and proteolysis. This autophagy-stimulated, KLHL20-dependent ULK1 degradation restrains the amplitude and duration of autophagy. Additionally, KLHL20 governs the degradation of ATG13, VPS34, Beclin-1, and ATG14 in prolonged starvation through a direct or indirect mechanism. Impairment of KLHL20-mediated regulation of autophagy dynamics potentiates starvation-induced cell death and aggravates diabetes-associated muscle atrophy. Our study identifies a key role of KLHL20 in autophagy termination by controlling autophagy-dependent turnover of ULK1 and VPS34 complex subunits and reveals the pathophysiological functions of this autophagy termination mechanism.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Animals, Apoptosis Regulatory Proteins, Autophagy, Autophagy-Related Protein-1 Homolog, Autophagy-Related Proteins, Beclin-1, Carrier Proteins, Class III Phosphatidylinositol 3-Kinases, Cullin Proteins, Diabetes Complications, Feedback, Physiological, HEK293 Cells, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Muscular Atrophy, Phosphorylation, Protein Serine-Threonine Kinases, Protein Transport, Proteolysis, RNA Interference, Signal Transduction, Time Factors, Transfection, Ubiquitin-Protein Ligases, Ubiquitination, Vesicular Transport Proteins
Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Animals, Apoptosis Regulatory Proteins, Autophagy, Autophagy-Related Protein-1 Homolog, Autophagy-Related Proteins, Beclin-1, Carrier Proteins, Class III Phosphatidylinositol 3-Kinases, Cullin Proteins, Diabetes Complications, Feedback, Physiological, HEK293 Cells, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Muscular Atrophy, Phosphorylation, Protein Serine-Threonine Kinases, Protein Transport, Proteolysis, RNA Interference, Signal Transduction, Time Factors, Transfection, Ubiquitin-Protein Ligases, Ubiquitination, Vesicular Transport Proteins
Mol Cell
Date: Jan. 07, 2016
PubMed ID: 26687681
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