Primary cilia are enriched in signaling receptors, and defects in their formation or function can induce conditions such as polycystic kidney disease, postaxial hexadactyly, and microphthalmia. Mammalian Hedgehog (Hh) signaling is important in the development of primary cilia, and TMEM216, a transmembrane protein that localizes to the base of cilia, is also implicated in ciliogenesis in zebrafish. Here, we found that Tmem216 -deficient mice had impaired Hh signaling and displayed typical ciliopathic phenotypes. These phenomena were also observed in cells deficient in TMEM216. Furthermore, TMEM216 interacted with core Hh signaling proteins, including SUFU, a negative regulator of Hh, and GLI2/GLI3, transcription factors downstream of Hh. The competition between TMEM216 and SUFU for binding to GLI2/GLI3 inhibited the cleavage of GLI2/GLI3 into their repressor forms, which resulted in the nuclear accumulation of full-length GLI2 and the decreased nuclear localization of cleaved GLI3, ultimately leading to the activation of Hh signaling. Together, these data suggest that the TMEM216-SUFU-GLI2/GLI3 axis plays a role in TMEM216 deficiency–induced ciliopathies and Hh signaling abnormalities.

中文翻译：

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TMEM216 通过 SUFU-GLI2/GLI3 轴促进初级纤毛发生和 Hedgehog 信号传导

初级纤毛富含信号受体，其形成或功能缺陷可诱发多囊肾病、轴后六指畸形和小眼症等疾病。哺乳动物 Hedgehog (Hh) 信号传导在初级纤毛的发育中非常重要，而 TMEM216（一种定位于纤毛基部的跨膜蛋白）也与斑马鱼的纤毛发生有关。在这里，我们发现TMEM216-缺陷小鼠的Hh信号传导受损并表现出典型的纤毛病表型。在 TMEM216 缺陷的细胞中也观察到了这些现象。此外，TMEM216 与核心 Hh 信号蛋白相互作用，包括 Hh 的负调节因子 SUFU 和 Hh 下游的转录因子 GLI2/GLI3。TMEM216 和 SUFU 之间竞争与 GLI2/GLI3 的结合抑制了 GLI2/GLI3 裂解为其阻遏物形式，导致全长 GLI2 的核积累和裂解的 GLI3 的核定位减少，最终导致激活嗯发出信号。总之，这些数据表明 TMEM216-SUFU-GLI2/GLI3 轴在 TMEM216 缺陷引起的纤毛病和 Hh 信号异常中发挥作用。