title: A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy.
abstract: Mitochondrial autophagy, or mitophagy, is a major mechanism involved in mitochondrial quality control via selectively removing damaged or unwanted mitochondria. Interactions between LC3 and mitophagy receptors such as FUNDC1, which harbors an LC3-interacting region (LIR), are essential for this selective process. However, how mitochondrial stresses are sensed to activate receptor-mediated mitophagy remains poorly defined. Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation. Our results reveal a mechanistic signaling pathway linking mitochondria-damaging signals to the dephosphorylation of FUNDC1 by PGAM5, which ultimately induces mitophagy.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Han
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China; Key Laboratory of Age-Associated Cardiac-Cerebral Vascular Disease of Guangdong Province, Institute of Neurology, Guangdong Medical College, Zhanjiang 524001, Guangdong Province, China.
authors.forename: Du
authors.initials: D
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Linbo
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Changqian
authors.initials: C
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Changying
authors.initials: C
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Liangwei
authors.initials: L
authors.lastname: Duan
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Xinqi
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Yuequan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: zhuys@nankai.edu.cn.
authors.forename: Yushan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China; State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: chenq@ioz.ac.cn.
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D047390:Casein Kinase II / Q000378:metabolism*; D016384:Consensus Sequence; D025461:Feedback, Physiological; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D063306:Mitophagy; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational
chemical_list: D002352:Carrier Proteins; C571016:FUNDC1 protein, human; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D047390:Casein Kinase II; C529563:PGAM5 protein, human; D010749:Phosphoprotein Phosphatases