Protein acetylation derepresses Serotonin Synthesis to potentiate Pancreatic Beta-Cell Function through HDAC1-PKA-Tph1 signaling
Protein acetylation derepresses Serotonin Synthesis to potentiate Pancreatic Beta-Cell Function through HDAC1-PKA-Tph1 signaling
复制标题
蛋白质乙酰化可抑制血清素合成，通过 HDAC1-PKA-Tph1 信号传导增强胰腺 Beta 细胞功能
DOI：
10.7150/thno.44459
复制
发表时间：
2020-06
期刊：
影响因子：
12.4
通讯作者：
Wang Xiao
中科院分区：
文献类型：
--
作者：
Zhang Yuqing;Wang Shushu;Zhang Linlin;Zhou Feiye;Zhu Kecheng;Zhu Qin;Liu Qianqian;Liu Yun;Jiang Lei;Ning Guang;Bi Yufang;Zhou Libin;Wang Xiao
理由：蛋白质乙酰化与转录控制和能量代谢紧密相关，但是，蛋白质乙酰化在胰岛功能中的作用仍然存在。
Rationale: Protein acetylation is tightly linked to transcriptional control and energy metabolism. However, the role of protein acetylation in islet function remains enigmatic. This study aims to determine how protein acetylation controls β-cell function and explore the underlying mechanism.Methods: The gene-expression profiles were analyzed for rat islets in response to two histone deacetylase (HDAC) inhibitors. Insulin secretion, tryptophan hydroxylase 1 (Tph1) expression, and serotonin synthesis of rat islets were detected after HDAC inhibitor treatment both in vivo and ex vivo. β-cell-specific Tph1-overexpressing transgenic rats and β-cell-specific Tph1 knockout mice were constructed to evaluate the role of Tph1 in β-cell function. The deacetylation of PKA in β-cells by HDAC1 was investigated by adenoviral infection, immunoprecipitation, and western blot.Results: Inhibition of HDACs greatly potentiated pancreatic β-cell function and reprogrammed transcriptional landscape of islets. Among the commonly up-regulated genes by two pan-HDAC inhibitors, Tph1 displayed the most prominent change. Specifically, inhibition of HDAC1 and HDAC3 by MS-275 strongly promoted Tph1 expression and endogenous serotonin synthesis in rat islets, concomitantly with enhanced insulin secretory capacity in vivo and ex vivo. β-cell-specific Tph1-overexpressing transgenic rats exhibited improved glucose tolerance and amplified glucose-stimulated insulin secretion. On the contrary, β-cell-specific Tph1 knockout mice displayed glucose intolerance and impaired insulin secretion with aging. Moreover, depletion of Tph1 in β-cells abrogated MS-275-induced insulin hypersecretion. Overexpression of HDAC1, not HDAC3, inhibited Tph1 transcriptional activity and decreased MS-275-stimulated Tph1 expression. Mechanistically, HDAC1 deacetylated PKA catalytic subunit and decreased its activity, resulting in Tph1 transcriptional repression. The acetylation mimetic K62Q mutant of PKA increased its catalytic activity. HDAC1 inhibition exerted a synergistic effect with cAMP/PKA signal on Tph1 expression.Conclusions: The present findings highlight a novel role of HDAC1-PKA-Tph1 signaling in governing β-cell functional compensation by derepressing serotonin synthesis.
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赖氨酸乙酰化：与其他翻译后修饰的编码串扰。
影响因子：
16
作者：
Yang, Xiang-Jiao;Seto, Edward
通讯作者：
Seto, Edward
细胞内5-羟色胺通过蛋白质素化调节胰腺β细胞的胰岛素分泌。
影响因子：
9.8
作者：
Paulmann N;Grohmann M;Voigt JP;Bert B;Vowinckel J;Bader M;Skelin M;Jevsek M;Fink H;Rupnik M;Walther DJ
通讯作者：
Walther DJ
影响因子：
7.7
作者：
Ohta Y;Kosaka Y;Kishimoto N;Wang J;Smith SB;Honig G;Kim H;Gasa RM;Neubauer N;Liou A;Tecott LH;Deneris ES;German MS
通讯作者：
German MS
影响因子：
7.7
作者：
Gregg T;Poudel C;Schmidt BA;Dhillon RS;Sdao SM;Truchan NA;Baar EL;Fernandez LA;Denu JM;Eliceiri KW;Rogers JD;Kimple ME;Lamming DW;Merrins MJ
通讯作者：
Merrins MJ
影响因子：
8.2
作者：
Schraenen, A.;Lemaire, K.;de Faudeur, G.;Hendrickx, N.;Granvik, M.;Van Lommel, L.;Mallet, J.;Vodjdani, G.;Gilon, P.;Binart, N.;in't Veld, P.;Schuit, F.
通讯作者：
Schuit, F.