Tmem138 is localized to the connecting cilium essential for rhodopsin localization and outer segment biogenesis.
Tmem138 is localized to the connecting cilium essential for rhodopsin localization and outer segment biogenesis.
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DOI：
10.1073/pnas.2109934119
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发表时间：
2022-04-12
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
光感受器的连接纤毛（CC）为外节（OS）蛋白的运输提供了唯一的途径。OS蛋白转运的失败导致退行性光感受器疾病，包括视网膜色素变性。我们证明，Tmem138，一种与纤毛病变相关的蛋白质，定位于感光细胞CC。Tmem138的种系缺失废除了OS形态发生，随后是快速的感光细胞退化。Tmem138与视紫红质和另外两种CC隔室蛋白Ahi1和Tmem231相互作用，可能形成膜复合物以促进视紫红质和其他OS结合蛋白穿过CC的运输。因此，该研究暗示了通过与CC膜复合物相互作用对OS蛋白递送的新的调节路线，并提供了对感光体纤毛病变疾病的见解。光感受器连接纤毛（CC）在结构上类似于初级纤毛的过渡区（TZ），并控制内外段（OS）之间的分子运输。具有潜在CC缺陷的视网膜营养不良表现为一系列广泛的被称为纤毛病的综合征病症以及非综合征性视网膜变性。尽管有广泛的研究，许多问题仍然存在于整个感光细胞CC的蛋白质运输的机制。在这里，我们基因失活小鼠Tmem138，一个基因编码一个假定的跨膜蛋白定位于纤毛TZ和纤毛病变。Tmem138的种系缺失废除了OS形态发生，随后是快速的感光细胞退化。Tmem138被发现定位于光感受器CC，并且是将Ahi1定位于CC的远端子域所需的。在OS蛋白的检查组中，视紫红质在OS形态发生之前错误定位于整个突变体细胞体。消融Tmem138在成熟的杆重演的种系突变体的分子变化，导致失败的光盘更新和解体的OS。此外，Tmem138相互作用与视紫红质和相关蛋白Tmem231，后者的纤毛定位也改变了突变的光感受器。两者合计，这些结果表明Tmem138在CC的功能组织中起着至关重要的作用，这对于视紫红质定位和OS生物发生是必不可少的。
The connecting cilium (CC) of the photoreceptor provides the only route for the trafficking of the outer segment (OS) proteins. Failure of OS protein transport causes degenerative photoreceptor diseases, including retinitis pigmentosa. We demonstrate that Tmem138, a protein linked to ciliopathy, is localized to the photoreceptor CC. Germline deletion of Tmem138 abolished OS morphogenesis, followed by rapid photoreceptor degeneration. Tmem138 interacts with rhodopsin and two additional CC compartment proteins, Ahi1 and Tmem231, likely forming a membrane complex to facilitate trafficking of rhodopsin and other OS-bound proteins across the CC. The study thus implicates a new line of regulation on the delivery of OS proteins through interactions with CC membrane complex(es) and provides insights into photoreceptor ciliopathy diseases. Photoreceptor connecting cilium (CC) is structurally analogous to the transition zone (TZ) of primary cilia and gates the molecular trafficking between the inner and the outer segment (OS). Retinal dystrophies with underlying CC defects are manifested in a broad array of syndromic conditions known as ciliopathies as well as nonsyndromic retinal degenerations. Despite extensive studies, many questions remain in the mechanism of protein trafficking across the photoreceptor CC. Here, we genetically inactivated mouse Tmem138, a gene encoding a putative transmembrane protein localized to the ciliary TZ and linked to ciliopathies. Germline deletion of Tmem138 abolished OS morphogenesis, followed by rapid photoreceptor degeneration. Tmem138 was found localized to the photoreceptor CC and was required for localization of Ahi1 to the distal subdomain of the CC. Among the examined set of OS proteins, rhodopsin was mislocalized throughout the mutant cell body prior to OS morphogenesis. Ablation of Tmem138 in mature rods recapitulated the molecular changes in the germline mutants, causing failure of disc renewal and disintegration of the OS. Furthermore, Tmem138 interacts reciprocally with rhodopsin and a related protein Tmem231, and the ciliary localization of the latter was also altered in the mutant photoreceptors. Taken together, these results suggest a crucial role of Tmem138 in the functional organization of the CC, which is essential for rhodopsin localization and OS biogenesis.
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影响因子：
4.4
作者：
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