title: Cytosolic PINK1 promotes the targeting of ubiquitinated proteins to the aggresome-autophagy pathway during proteasomal stress.
abstract: During proteasomal stress, cells can alleviate the accumulation of polyubiquitinated proteins by targeting them to perinuclear aggresomes for autophagic degradation, but the mechanism underlying the activation of this compensatory pathway remains unclear. Here we report that PINK1-s, a short form of Parkinson disease (PD)-related protein kinase PINK1 (PTEN induced putative kinase 1), is a major regulator of aggresome formation. PINK1-s is extremely unstable due to its recognition by the N-end rule pathway, and tends to accumulate in the cytosol during proteasomal stress. Overexpression of PINK1-s induces aggresome formation in cells with normal proteasomal activities, while loss of PINK1-s function leads to a significant decrease in the efficiency of aggresome formation induced by proteasomal inhibition. PINK1-s exerts its effect through phosphorylation of the ubiquitin-binding protein SQSTM1 (sequestosome 1) and increasing its ability to sequester polyubiquitinated proteins into aggresomes. These findings pinpoint PINK1-s as a sensor of proteasomal activities that transduces the proteasomal impairment signal to the aggresome formation machinery.
authors.affiliation: a Department of Pediatrics , West China 2nd University Hospital, Sichuan University , Chengdu , Sichuan , China.|b Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University , Chengdu , Sichuan , China.|c Shenzhen Key Laboratory for Molecular Biology of Neural Development, Laboratory of Developmental and Regenerative Biology, Institute of Biomedicine & Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen , Guangdong , China.
authors.forename: Ju
authors.initials: J
authors.lastname: Gao
authors.affiliation: a Department of Pediatrics , West China 2nd University Hospital, Sichuan University , Chengdu , Sichuan , China.|b Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University , Chengdu , Sichuan , China.|d State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , Sichuan , China.
authors.forename: Mengen
authors.initials: M
authors.lastname: Li
authors.affiliation: a Department of Pediatrics , West China 2nd University Hospital, Sichuan University , Chengdu , Sichuan , China.|b Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University , Chengdu , Sichuan , China.
authors.forename: Siyue
authors.initials: S
authors.lastname: Qin
authors.affiliation: a Department of Pediatrics , West China 2nd University Hospital, Sichuan University , Chengdu , Sichuan , China.|b Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University , Chengdu , Sichuan , China.|d State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , Sichuan , China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: a Department of Pediatrics , West China 2nd University Hospital, Sichuan University , Chengdu , Sichuan , China.|b Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University , Chengdu , Sichuan , China.|d State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , Sichuan , China.
authors.forename: Sicong
authors.initials: S
authors.lastname: Jiang
authors.affiliation: a Department of Pediatrics , West China 2nd University Hospital, Sichuan University , Chengdu , Sichuan , China.|b Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University , Chengdu , Sichuan , China.|d State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , Sichuan , China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: a Department of Pediatrics , West China 2nd University Hospital, Sichuan University , Chengdu , Sichuan , China.|b Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University , Chengdu , Sichuan , China.
authors.forename: Yongkang
authors.initials: Y
authors.lastname: Deng
authors.affiliation: a Department of Pediatrics , West China 2nd University Hospital, Sichuan University , Chengdu , Sichuan , China.|b Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University , Chengdu , Sichuan , China.
authors.forename: Chenliang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: a Department of Pediatrics , West China 2nd University Hospital, Sichuan University , Chengdu , Sichuan , China.|b Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University , Chengdu , Sichuan , China.|d State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , Sichuan , China.
authors.forename: Dujuan
authors.initials: D
authors.lastname: You
authors.affiliation: c Shenzhen Key Laboratory for Molecular Biology of Neural Development, Laboratory of Developmental and Regenerative Biology, Institute of Biomedicine & Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen , Guangdong , China.
authors.forename: Hongchang
authors.initials: H
authors.lastname: Li
authors.affiliation: a Department of Pediatrics , West China 2nd University Hospital, Sichuan University , Chengdu , Sichuan , China.|b Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University , Chengdu , Sichuan , China.
authors.forename: Dezhi
authors.initials: D
authors.lastname: Mu
authors.affiliation: e State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University , Changsha , Hunan , China.
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: a Department of Pediatrics , West China 2nd University Hospital, Sichuan University , Chengdu , Sichuan , China.|b Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University , Chengdu , Sichuan , China.|c Shenzhen Key Laboratory for Molecular Biology of Neural Development, Laboratory of Developmental and Regenerative Biology, Institute of Biomedicine & Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen , Guangdong , China.|d State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , Sichuan , China.
authors.forename: Changan
authors.initials: C
authors.lastname: Jiang
mesh_terms: D001343:Autophagy; D016923:Cell Death; D019610:Cytoprotection; D003600:Cytosol / Q000201:enzymology*; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D066329:Protein Aggregates; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D013312:Stress, Physiological; D025801:Ubiquitin / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D008239:Lysine; D010768:Phosphoserine; D046988:Proteasome Endopeptidase Complex; D066329:Protein Aggregates; D020033:Protein Isoforms; D011494:Protein Kinases; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin; D057149:Ubiquitinated Proteins; D000099202:PTEN-Induced Putative Kinase; C099718:SQSTM1 protein, human
keywords: Aggresome; PINK1; SQSTM1; autophagy; proteasomal inhibition