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

• Published in: Genes & diseases Vol. 11; no. 2; pp. 1035 - 1049
• Main Authors: Sun, Kuanxiang, Liu, Lu, Jiang, Xiaoyan, Wang, Heting, Wang, Lin, Yang, Yeming, Liu, Wenjing, Zhang, Lin, Zhao, Xiaohui, Zhu, Xianjun
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-03-2024; Chongqing Medical University; KeAi Communications Co., Ltd
• Subjects: ANO2; Cilium; EMC6; ER membrane protein complex; Full Length; Mislocalization; Photoreceptor degeneration; TMEM67; ER membrane protein complex; Cilium; Photoreceptor degeneration; TMEM67; EMC6; Mislocalization; ANO2
• ISSN: 2352-3042; 2352-4820; 2352-3042
• DOI: 10.1016/j.gendis.2023.03.033

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 photoreceptors. 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 proteins 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' ciliogenesis by regulating the synthesis of membrane proteins associated with cilia, contributing to the mislocalization of membrane disc proteins.