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

Liu, Chin-Chih, Lin, Yu-Ching, Chen, Yu-Hsuan, Chen, Chun-Ming, Pang, Liang-Yu, Chen, Hsuan-An, Wu, Pei-Rung, Lin, Mei-Yao, Jiang, Si-Tse, Tsai, Ting-Fen, Chen, Ruey-Hwa·2016·Molecular Cell
DOI 10.1016/j.molcel.2015.11.001
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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.

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Metadata

Authors
Liu, C.-C., Lin, Y.-C., Chen, Y.-H., Chen, C.-M., Pang, L.-Y., Chen, H.-A., Wu, P.-R., Lin, M.-Y., Jiang, S.-T., Tsai, T.-F., & Chen, R.-H.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2016-01
Volume
61
Issue
1
Pages
84-97
ISSN
1097-2765
DOI
10.1016/j.molcel.2015.11.001
Cited by
215
References
12
Language
en
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