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Mol Cell. 2016 Jan 7;61(1):84-97. doi: 10.1016/j.molcel.2015.11.001. Epub 2015 Dec 10.

Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination.

Author information

1
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
2
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
3
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
4
Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
5
Department of Life Sciences and Institute of Genome Sciences, National Yang Ming University, Taipei 112, Taiwan.
6
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan; Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan. Electronic address: rhchen@gate.sinica.edu.tw.

Abstract

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.

KEYWORDS:

ULK1; VPS34 complex; autophagy; ubiquitination

PMID:
26687681
DOI:
10.1016/j.molcel.2015.11.001
[Indexed for MEDLINE]
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