Chemical Genetics Reveals a Role of Squalene Synthase in TGFβ Signaling and Cardiomyogenesis,Angewandte Chemie International Edition

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Chemical Genetics Reveals a Role of Squalene Synthase in TGFβ Signaling and Cardiomyogenesis
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2021-08-10 , DOI: 10.1002/anie.202100523
Yasushi Takemoto ₁ , Shin Kadota ₂ , Itsunari Minami ₃ , Shinya Otsuka ₁ , Satoshi Okuda ₁ , Masahiro Abo ₁ , Louvy Lynn Punzalan ₁ , Yan Shen ₁ , Yuji Shiba ₂ , Motonari Uesugi _{1,

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Affiliation

KY02111 is a widely used small molecule that boosts cardiomyogenesis of the mesoderm cells derived from pluripotent stem cells, yet its molecular mechanism of action remains elusive. The present study resolves the initially perplexing effects of KY02111 on Wnt signaling and subsequently identifies squalene synthase (SQS) as a molecular target of KY02111 and its optimized version, KY-I. By disrupting the interaction of SQS with cardiac ER-membrane protein TMEM43, KY02111 impairs TGFβ signaling, but not Wnt signaling, and thereby recapitulates the clinical mutation of TMEM43 that causes arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart disease that involves a substitution of myocardium with fatty tissue. These findings reveal a heretofore undescribed role of SQS in TGFβ signaling and cardiomyogenesis. KY02111 may find its use in ARVC modeling as well as serve as a chemical tool for studying TGFβ/SMAD signaling.

中文翻译：

化学遗传学揭示角鲨烯合酶在 TGFβ 信号传导和心肌生成中的作用

KY02111 是一种广泛使用的小分子，可促进源自多能干细胞的中胚层细胞的心肌生成，但其分子作用机制仍然难以捉摸。本研究解决了 KY02111 对 Wnt 信号传导的最初令人困惑的影响，随后将角鲨烯合酶 (SQS) 确定为 KY02111 及其优化版本 KY-I 的分子靶标。通过破坏 SQS 与心脏内质网膜蛋白 TMEM43 的相互作用，KY02111 会损害 TGFβ 信号传导，但不会损害 Wnt 信号传导，从而重现导致致心律失常性右心室心肌病 (ARVC) 的 TMEM43 临床突变，这是一种涉及替代的遗传性心脏病具有脂肪组织的心肌。这些发现揭示了 SQS 在 TGFβ 信号传导和心肌发生中迄今未描述的作用。

更新日期：2021-09-20

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