title: RACK1 Promotes Autophagy by Enhancing the Atg14L-Beclin 1-Vps34-Vps15 Complex Formation upon Phosphorylation by AMPK.
abstract: Autophagy is essential for maintaining tissue homeostasis. Although adaptors have been demonstrated to facilitate the assembly of the Atg14L-Beclin 1-Vps34-Vps15 complex, which functions in autophagosome formation, it remains unknown whether the autophagy machinery actively recruits such adaptors. WD40-repeat proteins are a large, highly conserved family of adaptors implicated in various cellular activities. However, the role of WD40-repeat-only proteins, such as RACK1, in postnatal mammalian physiology remains unknown. Here, we report that hepatocyte-specific RACK1 deficiency leads to lipid accumulation in the liver, accompanied by impaired Atg14L-linked Vps34 activity and autophagy. Further exploration indicates that RACK1 participates in the formation of autophagosome biogenesis complex upon its phosphorylation by AMPK at Thr50. Thr50 phosphorylation of RACK1 enhances its direct binding to Vps15, Atg14L, and Beclin 1, thereby promoting the assembly of the autophagy-initiation complex. These observations provide insight into autophagy induction and establish a pivotal role for RACK1 in postnatal mammalian physiology.
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PRC; Key Laboratory of Cellular and Molecular Immunology, Henan University, Kaifeng, Henan 475001, PRC.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PRC.
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PRC.
authors.forename: Guihua
authors.initials: G
authors.lastname: Qiu
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PRC; Key Laboratory of Cellular and Molecular Immunology, Henan University, Kaifeng, Henan 475001, PRC.
authors.forename: Silei
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PRC.
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Jing
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PRC.
authors.forename: Jingyang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PRC; Key Laboratory of Cellular and Molecular Immunology, Henan University, Kaifeng, Henan 475001, PRC.
authors.forename: Wendie
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PRC.
authors.forename: Junxia
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PRC.
authors.forename: Kun
authors.initials: K
authors.lastname: Han
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PRC.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PRC.
authors.forename: Beifen
authors.initials: B
authors.lastname: Shen
authors.affiliation: Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Science Center, Beijing 100083, PRC.
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathophysiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, PRC.
authors.forename: Weiping J
authors.initials: WJ
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cellular and Molecular Immunology, Henan University, Kaifeng, Henan 475001, PRC.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PRC. Electronic address: zhangjy@nic.bmi.ac.cn.
authors.forename: Jiyan
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D009479:Neuropeptides / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D000075370:Receptors for Activated C Kinase; D058571:Vacuolar Sorting Protein VPS15 / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C561107:Atg14 protein, mouse; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D046912:Multiprotein Complexes; D009479:Neuropeptides; C090294:RACK1 protein, mouse; D000075370:Receptors for Activated C Kinase; D033921:Vesicular Transport Proteins; D058546:Class III Phosphatidylinositol 3-Kinases; D058571:Vacuolar Sorting Protein VPS15; D000263:Adenylate Kinase