title: KLHL20 links the ubiquitin-proteasome system to autophagy termination.
abstract: Autophagy is a dynamic and self-limiting process. The amplitude and duration of this process need to be properly controlled to maintain cell homeostasis, and excessive or insufficient autophagy activity could each lead to disease states. Compared to our understanding of the molecular mechanisms of autophagy induction, little is known about how the autophagy process is turned off after its activation. We recently identified KLHL20 as a key regulator of autophagy termination. By functioning as a substrate-binding subunit of CUL3 ubiquitin ligase, KLHL20 targets the activated ULK1 and phagophore-residing PIK3C3/VPS34 and BECN1 for ubiquitination and proteasomal degradation, which in turn triggers a destabilization of their complex components ATG13 and ATG14. These hierarchical degradation events cause the exhaustion of the autophagic pool of ULK1 and PIK3C3/VPS34 complexes, thereby preventing persistent and excessive autophagy activity. Impairment of KLHL20-dependent feedback regulation of autophagy enhances cell death under prolonged starvation and aggravates muscle atrophy in diabetic mice, which highlights the pathophysiological significance of this autophagy termination mechanism in cell survival and tissue homeostasis. Modulation of this autophagy termination pathway may be effective for treating diseases associated with deregulation of autophagy activity.
authors.affiliation: a Institute of Biological Chemistry, Academia Sinica, Institute of Biochemical Sciences, College of Life Science, National Taiwan University , Taipei , Taiwan.
authors.forename: Chin-Chih
authors.initials: CC
authors.lastname: Liu
authors.affiliation: a Institute of Biological Chemistry, Academia Sinica, Institute of Biochemical Sciences, College of Life Science, National Taiwan University , Taipei , Taiwan.
authors.forename: Ruey-Hwa
authors.initials: RH
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C550011:KLHL20 protein, human; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: CUL3-KLHL20 ubiquitin ligase; ULK1; VPS34 complex; autophagy termination; ubiquitin-proteasome system