title: Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination.
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.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Chin-Chih
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Liang-Yu
authors.initials: LY
authors.lastname: Pang
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Hsuan-An
authors.initials: HA
authors.lastname: Chen
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Pei-Rung
authors.initials: PR
authors.lastname: Wu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Mei-Yao
authors.initials: MY
authors.lastname: Lin
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Si-Tse
authors.initials: ST
authors.lastname: Jiang
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang Ming University, Taipei 112, Taiwan.
authors.forename: Ting-Fen
authors.initials: TF
authors.lastname: Tsai
authors.affiliation: 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.
authors.forename: Ruey-Hwa
authors.initials: RH
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D058546:Class III Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D048909:Diabetes Complications / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D025461:Feedback, Physiological; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009133:Muscular Atrophy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: C539000:ATG14 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; C561107:Atg14 protein, mouse; D000071183:Autophagy-Related Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C503645:CUL3 protein, human; D002352:Carrier Proteins; C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D047908:Intracellular Signaling Peptides and Proteins; C550011:KLHL20 protein, human; C000607811:KLHL20 protein, mouse; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; D044767:Ubiquitin-Protein Ligases; D058546:Class III Phosphatidylinositol 3-Kinases; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; C112444:Ulk1 protein, mouse
keywords: ULK1; VPS34 complex; autophagy; ubiquitination