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- Title
TMEM216 promotes primary ciliogenesis and Hedgehog signaling through the SUFU-GLI2/GLI3 axis.
- Authors
Wang, Yingying; Yao, Huili; Zhang, Yu; Mu, Ning; Lu, Tong; Du, Zhiyuan; Wu, Yingdi; Li, Xiaopeng; Su, Min; Shao, Ming; Sun, Xiaoyang; Su, Ling; Liu, Xiangguo
- Abstract
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. Editor's summary: The normal development of primary cilia is necessary for signal transduction, particularly Hedgehog (Hh) signaling, and impaired ciliogenesis underlies various developmental disorders. Noting that the transmembrane protein TMEM216 is implicated in ciliogenesis in zebrafish, Wang et al. found that Tmem216−/− mice had impaired ciliogenesis and reduced Hh signaling. TMEM216 competed with a negative regulator of Hh signaling, SUFU, for binding to GLI transcription factors, inhibiting the cleavage of GLI2/GLI3 into their repressor forms, thus promoting Hh signaling. Together, these findings delineate how TMEM216 promotes Hh signaling during ciliogenesis. —Amy E. Baek
- Subjects
HEDGEHOG signaling proteins; POLYCYSTIC kidney disease; MEMBRANE proteins; TRANSCRIPTION factors; CELLULAR signal transduction
- Publication
Science Signaling, 2024, Vol 17, Issue 820, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abo0465