title: The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy.
abstract: Autophagy-dependent clearance of ubiquitinated and aggregated proteins is critical to protein quality control, but the underlying mechanisms are not well understood. Here, we report the essential role of the BEACH (beige and Chediak-Higashi) and WD40 repeat-containing protein WDR81 in eliminating ubiquitinated proteins through autophagy. WDR81 associates with ubiquitin (Ub)-positive protein foci, and its loss causes accumulation of Ub proteins and the autophagy cargo receptor p62. WDR81 interacts with p62, facilitating recognition of Ub proteins by p62. Furthermore, WDR81 interacts with LC3C through canonical LC3-interacting regions in the BEACH domain, promoting LC3C recruitment to ubiquitinated proteins. Inactivation of LC3C or defective autophagy results in accumulation of Ub protein aggregates enriched for WDR81. In mice, WDR81 inactivation causes accumulation of p62 bodies in cortical and striatal neurons in the brain. These data suggest that WDR81 coordinates p62 and LC3C to facilitate autophagic removal of Ub proteins, and provide important insights into CAMRQ2 syndrome, a WDR81-related developmental disorder.
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming 650091, China.|Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming 650091, China.
authors.forename: Xuezhao
authors.identifier: 0000-0001-7297-1429
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yang
authors.identifier: 0000-0002-6286-2939
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming 650091, China.|Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming 650091, China.
authors.forename: Xin
authors.identifier: 0000-0003-4895-6565
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|Graduate School, University of Chinese Academy of Sciences, Beijing 100093, China.
authors.forename: Ruxiao
authors.initials: R
authors.lastname: Xing
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Kai
authors.identifier: 0000-0001-9540-3053
authors.initials: K
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|Graduate School, University of Chinese Academy of Sciences, Beijing 100093, China.
authors.forename: Qiwen
authors.identifier: 0000-0001-6743-3191
authors.initials: Q
authors.lastname: Gan
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|Graduate School, University of Chinese Academy of Sciences, Beijing 100093, China.
authors.forename: Changyong
authors.initials: C
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Zhiyang
authors.initials: Z
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Youli
authors.identifier: 0000-0001-8764-9344
authors.initials: Y
authors.lastname: Jian
authors.affiliation: Peninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, Plymouth University, Plymouth PL6 8BU, England, UK.
authors.forename: Shouqing
authors.identifier: 0000-0002-7998-3059
authors.initials: S
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China wxguo@genetics.ac.cn.
authors.forename: Weixiang
authors.initials: W
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China clyang@genetics.ac.cn.|State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming 650091, China.|Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming 650091, China.
authors.forename: Chonglin
authors.identifier: 0000-0002-4104-7855
authors.initials: C
authors.lastname: Yang
mesh_terms: D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D066329:Protein Aggregates; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: C502071:MAP1LC3C protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C118585:P62 protein, human; D066329:Protein Aggregates; D016601:RNA-Binding Proteins; C000609634:WDR81 protein, human