The EMBO journal · 2021
Inhibition of Syk promotes chemical reprogramming of fibroblasts via metabolic rewiring and H2 S production.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Wang Weiyun, Ren Shaofang, Lu Yunkun, Chen Xi, Qu Juanjuan, Ma Xiaojie, Deng Qian, Hu Zhensheng, Jin Yan, Zhou Ziyu, Ge Wenyan, Zhu Yibing, Yang Nannan, Li Qin, Pu Jiaqi, Chen Guo, Ye Cunqi, Wang Hao, Zhao Xiaoyang, Liu Zhiqiang, Zhu Saiyong
Аннотация
Chemical compounds have recently been introduced as alternative and non-integrating inducers of pluripotent stem cell fate. However, chemical reprogramming is hampered by low efficiency and the molecular mechanisms remain poorly characterized. Here, we show that inhibition of spleen tyrosine kinase (Syk) by R406 significantly promotes mouse chemical reprogramming. Mechanistically, R406 alleviates Syk / calcineurin (Cn) / nuclear factor of activated T cells (NFAT) signaling-mediated suppression of glycine, serine, and threonine metabolic genes and dependent metabolites. Syk inhibition upregulates glycine level and downstream transsulfuration cysteine biosynthesis, promoting cysteine metabolism and cellular hydrogen sulfide (H2 S) production. This metabolic rewiring decreased oxidative phosphorylation and ROS levels, enhancing chemical reprogramming. In sum, our study identifies Syk-Cn-NFAT signaling axis as a new barrier of chemical reprogramming and suggests metabolic rewiring and redox homeostasis as important opportunities for controlling cell fates.