Chemical Genetics Reveals a Role of Squalene Synthase in TGFβ Signaling and Cardiomyogenesis.

Autor: Takemoto Y; Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan., Kadota S; Institute for Biomedical Sciences, Shinshu University, Matsumoto, Nagano, 390-8621, Japan., Minami I; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, 606-8501, Japan., Otsuka S; Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan., Okuda S; Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan., Abo M; Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan., Punzalan LL; Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan., Shen Y; Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan., Shiba Y; Institute for Biomedical Sciences, Shinshu University, Matsumoto, Nagano, 390-8621, Japan., Uesugi M; Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan.; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, 606-8501, Japan.; School of Pharmacy, Fudan University, Shanghai, 201203, China.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2021 Sep 27; Vol. 60 (40), pp. 21824-21831. Date of Electronic Publication: 2021 Aug 26.
DOI: 10.1002/anie.202100523
Abstrakt: 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.
(© 2021 Wiley-VCH GmbH.)
Databáze: MEDLINE
Externí odkaz: