Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430072, China.
State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou 325003, China.
Cell Rep. 2024 Apr 23;43(4):114010. doi: 10.1016/j.celrep.2024.114010. Epub 2024 Mar 26.
Although the small GTPase RAB37 acts as an organizer of autophagosome biogenesis, the upstream regulatory mechanism of autophagy via guanosine diphosphate (GDP)-guanosine triphosphate (GTP) exchange in maintaining retinal function has not been determined. We found that retinitis pigmentosa GTPase regulator (RPGR) is a guanine nucleotide exchange factor that activates RAB37 by accelerating GDP-to-GTP exchange. RPGR directly interacts with RAB37 via the RPGR-RCC1-like domain to promote autophagy through stimulating exchange. Rpgr knockout (KO) in mice leads to photoreceptor degeneration owing to autophagy impairment in the retina. Notably, the retinopathy phenotypes of Rpgr KO retinas are rescued by the adeno-associated virus-mediated transfer of pre-trans-splicing molecules, which produce normal Rpgr mRNAs via trans-splicing in the Rpgr KO retinas. This rescue upregulates autophagy through the re-expression of RPGR in KO retinas to accelerate GDP-to-GTP exchange; thus, retinal homeostasis reverts to normal. Taken together, these findings provide an important missing link for coordinating RAB37 GDP-GTP exchange via the RPGR and retinal homeostasis by autophagy regulation.
虽然小分子 GTPase RAB37 作为自噬体生物发生的组织者发挥作用，但通过鸟苷二磷酸 (GDP) - 鸟苷三磷酸 (GTP) 交换在维持视网膜功能方面的自噬的上游调节机制尚未确定。我们发现，视网膜色素变性 GTP 酶调节因子 (RPGR) 是一种鸟嘌呤核苷酸交换因子，通过加速 GDP 到 GTP 的交换来激活 RAB37。RPGR 通过刺激交换直接与 RAB37 相互作用，通过刺激交换促进自噬。小鼠中的 Rpgr 敲除 (KO) 导致光感受器退化，这是由于视网膜中的自噬受损。值得注意的是，腺相关病毒介导的前剪接分子转导可挽救 Rpgr KO 视网膜的视网膜病变表型，这些前剪接分子通过 Rpgr KO 视网膜中的反式剪接产生正常的 Rpgr mRNAs。这种挽救通过在 KO 视网膜中重新表达 RPGR 来上调自噬，从而加速 GDP 到 GTP 的交换；因此，视网膜的内稳态恢复正常。总之，这些发现为通过 RPGR 协调 RAB37 GDP-GTP 交换以及通过自噬调节维持视网膜内稳态提供了一个重要的缺失环节。
