4.6 Article

The 3-beta-hydroxysteroid-Delta(8), Delta(7)-isomerase EBP inhibits cholesterylation of Smoothened

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ELSEVIER
DOI: 10.1016/j.bbalip.2021.159041

关键词

SMO; Cholesterylation; Hedgehog signaling; EBP; CDPX2

资金

  1. National Natural Science Foundation, China (China) [91753204, 31690102, 91957103]
  2. Ministry of Science and Technology, China (China) [2018YFA0800700, 2019YFA0802701]
  3. 111 Project of Ministry of Education of China [B16036]
  4. Fountain-Valley Life Sciences Fund of University of Chinese Academy of Sciences Education Foundation
  5. Tencent Foundation through the XPLORER PRIZE

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The study identified Emopamil binding protein (EBP) as a protein that interacts with SMO, suppressing SMO cholesterylation and Hh pathway activity. EBP modulates SMO cholesterylation through direct binding, providing insights into the potential mechanism of CDPX2 pathogenesis.
Hedgehog (Hh) pathway plays a central role in vertebrate embryonic development and carcinogenesis. The G-protein coupled receptor-like protein Smoothened (SMO) is one of the major members in Hh pathway. Covalent modification of cholesterol on the 95th asparagine (D95) of human SMO, which is regulated by Hh and PTCH1, is critical for SMO activation. However, it is not known whether SMO cholesterylation is regulated by other proteins. In this study, we identified Emopamil binding protein (EBP, also known as 3-beta-hydroxysteroid-Delta(8), Delta(7)-isomerase) as a SMO-interacting protein. Overexpression of EBP suppressed SMO cholesterylation and Hh pathway activity, whereas genetic disruption of EBP enhanced SMO cholesterylation and the downstream signaling. EBP-mediated inhibition of SMO cholesterylation was independent of its isomerase activity, but dependent on the C-terminus of EBP that was required for SMO binding. The X-linked dominant chondrodysplasia punctate 2 (CDPX2)-associated EBP mutants inhibited SMO cholesterylation too. Together, this study shows that EBP modulates SMO cholesterylation through direct binding and suggests a possible mechanism of CDPX2 pathogenesis.

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