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

Chin Chih Liu, Yu Ching Lin, Yu Hsuan Chen, Chun Ming Chen, Liang Yu Pang, Hsuan An Chen, Pei Rung Wu, Mei Yao Lin, Si Tse Jiang, Ting Fen Tsai, Ruey Hwa Chen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

143 Scopus citations

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. Liu et al. report a function of the Cul3-KLHL20 ubiquitin ligase in a feedback regulation, leading to autophagy termination through the degradation of multiple subunits of ULK1 and VPS34 complexes. This mechanism is important for cell survival and muscle homeostasis.

Original languageEnglish
Pages (from-to)84-97
Number of pages14
JournalMolecular Cell
Volume61
Issue number1
DOIs
StatePublished - 7 Jan 2016

Keywords

  • Autophagy
  • Ubiquitination
  • ULK1
  • VPS34 complex

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