The endoplasmic reticulum membrane protein complex subunit Emc6 is essential for rhodopsin localization and photoreceptor cell survival

导出学术成果认领

摘要The endoplasmic reticulum(ER)membrane protein complex(EMC)is responsible for monitoring the biogenesis and synthetic quality of membrane proteins with tail-anchored or multiple transmembrane domains.The EMC subunit EMC6 is one of the core members of EMC and forms an enclosed hydrophilic vestibule in cooperation with EMC3.Despite studies demonstrating that deletion of EMC3 led to rhodopsin mislocalization in rod photoreceptors of mice,the precise mechanism leading to the failure of rhodopsin trafficking remains unclear.Here,we generated the first rod photoreceptor-specific knockout of Emc6(RKO)and cone photoreceptor-specific knockout of Emc6(CKO)mouse models.Deficiency of Emc6 in rod photoreceptors led to progressive shortening of outer segments(OS),impaired visual function,mislocalization and reduced expression of rhodopsin,and increased gliosis in rod photorecep-tors.In addition,CKO mice displayed the progressive death of cone photoreceptors and abnormal localization of cone opsin protein.Subsequently,proteomics analysis of the RKO mouse retina illustrated that several cilium-related proteins,particularly anoctamin-2(ANO2)and transmembrane protein 67(TMEM67),were significantly down-regulated prior to OS degeneration.Detrimental rod photoreceptor cilia and mislocalized membrane disc pro-teins were evident in RKO mice.Our data revealed that in addition to monitoring the synthesis of rhodopsin-dominated membrane disc proteins,EMC6 also impacted rod photoreceptors'ci-liogenesis by regulating the synthesis of membrane proteins associated with cilia,contributing to the mislocalization of membrane disc proteins.

作者 Kuanxiang Sun ^[1] Lu Liu ^[2] Xiaoyan Jiang ^[3] Heting Wang ^[4] Lin Wang ^[5] Yeming Yang Wenjing Liu Lin Zhang Xiaohui Zhao Xianjun Zhu 学术成果认领

作者单位 Health Management Center,Sichuan Provincial People's Hospital,University of Electronic Science and Technology of China,Chengdu,Sichuan 610072,China;Key Laboratory of Tibetan Medicine Research,Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research,Northwest Institute of Plateau Biology,Xining,Qinghai 810008,China;The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine,Center for Medical Genetics,Sichuan Provincial People's Hospital,University of Electronic Science and Technology of China,Chengdu,Sichuan 610072,China;Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences(2019RU026),Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital,Chengdu,Sichuan 610072,China ^[1] The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine,Center for Medical Genetics,Sichuan Provincial People's Hospital,University of Electronic Science and Technology of China,Chengdu,Sichuan 610072,China ^[2] Health Management Center,Sichuan Provincial People's Hospital,University of Electronic Science and Technology of China,Chengdu,Sichuan 610072,China ^[3] Key Laboratory of Tibetan Medicine Research,Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research,Northwest Institute of Plateau Biology,Xining,Qinghai 810008,China ^[4] Health Management Center,Sichuan Provincial People's Hospital,University of Electronic Science and Technology of China,Chengdu,Sichuan 610072,China;Key Laboratory of Tibetan Medicine Research,Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research,Northwest Institute of Plateau Biology,Xining,Qinghai 810008,China;The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine,Center for Medical Genetics,Sichuan Provincial People's Hospital,University of Electronic Science and Technology of China,Chengdu,Sichuan 610072,China;Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences(2019RU026),Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital,Chengdu,Sichuan 610072,China;Department of Ophthalmology,The First People's Hospital of Shangqiu,Shangqiu,Henan 476000,China ^[5]

DOI 10.1016/j.gendis.2023.03.033

发布时间 2024-04-18