内质网膜蛋白复合物亚单位6(endoplasmic reticulum membrane protein complex subunit 6,EMC6),也称穿膜蛋白93(transmembrane protein 93,TMEM93)是我们首次报道的一个人类自噬相关分子。EMC6基因进化保守,表达广泛,在胃癌组织中表达...内质网膜蛋白复合物亚单位6(endoplasmic reticulum membrane protein complex subunit 6,EMC6),也称穿膜蛋白93(transmembrane protein 93,TMEM93)是我们首次报道的一个人类自噬相关分子。EMC6基因进化保守,表达广泛,在胃癌组织中表达下调或缺失。本研究利用构建的重组腺病毒5型EMC6(Ad5-EMC6)载体,感染胃癌细胞系BGC823和SGC7901,分析了其在肿瘤细胞的表达以及抗肿瘤活性。研究证明,Ad5-EMC6能够显著抑制胃癌细胞的克隆形成、细胞划痕修复、以及迁移和侵袭的能力。进一步的研究提示,Ad5-EMC6能够降低胃癌细胞局部黏着斑激酶(FAK)的Y576/577磷酸化水平,FAK下游的基质金属蛋白酶MMP2和MMP9的蛋白质水平也同时下调。在裸鼠的腹膜扩散模型中,Ad5-EMC6处理组的小鼠腹膜结节数量明显减少或缺失。这些研究数据提示,Ad5-EMC6介导的FAK信号灭活可能是其抑瘤活性的机制之一,其分子机制还需要进一步探讨。展开更多
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 EM...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.展开更多
文摘内质网膜蛋白复合物亚单位6(endoplasmic reticulum membrane protein complex subunit 6,EMC6),也称穿膜蛋白93(transmembrane protein 93,TMEM93)是我们首次报道的一个人类自噬相关分子。EMC6基因进化保守,表达广泛,在胃癌组织中表达下调或缺失。本研究利用构建的重组腺病毒5型EMC6(Ad5-EMC6)载体,感染胃癌细胞系BGC823和SGC7901,分析了其在肿瘤细胞的表达以及抗肿瘤活性。研究证明,Ad5-EMC6能够显著抑制胃癌细胞的克隆形成、细胞划痕修复、以及迁移和侵袭的能力。进一步的研究提示,Ad5-EMC6能够降低胃癌细胞局部黏着斑激酶(FAK)的Y576/577磷酸化水平,FAK下游的基质金属蛋白酶MMP2和MMP9的蛋白质水平也同时下调。在裸鼠的腹膜扩散模型中,Ad5-EMC6处理组的小鼠腹膜结节数量明显减少或缺失。这些研究数据提示,Ad5-EMC6介导的FAK信号灭活可能是其抑瘤活性的机制之一,其分子机制还需要进一步探讨。
基金supported by The National Natural Science Foundation of China(No.82121003,81970841,82101160)the program of Science and Technology International Cooperation Project of Qinghai province(China)(No.2022-HZ-814)+2 种基金the CAMS Innovation Fund for Medical Sciences(No.2019-12M-5-032)Sichuan Intellectual Property Office(China)(No.2022-ZS-0070)the Department of Chengdu Science and Technology(Sichuan,China)(No.2021-YF05-01316-SN).
文摘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.
