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Reciprocal regulation of ROR?t acetylation and function by p300 and HDAC1.

ABSTRACT: T helper 17 (Th17) cells not only play critical roles in protecting against bacterial and fungal infections but are also involved in the pathogenesis of autoimmune diseases. The retinoic acid-related orphan receptor (ROR?t) is a key transcription factor involved in Th17 cell differentiation through direct transcriptional activation of interleukin 17(A) (IL-17). How ROR?t itself is regulated remains unclear. Here, we report that p300, which has histone acetyltransferase (HAT) activity, interacts with and acetylates ROR?t at its K81 residue. Knockdown of p300 downregulates ROR?t protein and ROR?t-mediated gene expression in Th17 cells. In addition, p300 can promote ROR?t-mediated transcriptional activation. Interestingly, the histone deacetylase (HDAC) HDAC1 can also interact with ROR?t and reduce its acetylation level. In summary, our data reveal previously unappreciated posttranslational regulation of ROR?t, uncovering the underlying mechanism by which the histone acetyltransferase p300 and the histone deacetylase HDAC1 reciprocally regulate the ROR?t-mediated transcriptional activation of IL-17.

SUBMITTER: Wu Q

PROVIDER: S-EPMC4817527 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Reciprocal regulation of RORγt acetylation and function by p300 and HDAC1.

Wu Qingsi Q Nie Jia J Gao Yayi Y Xu Peng P Sun Qijuan Q Yang Jing J Han Lei L Chen Zuojia Z Wang Xiuwen X Lv Ling L Tsun Andy A Shen Jijia J Li Bin B

Scientific reports 20151109

T helper 17 (Th17) cells not only play critical roles in protecting against bacterial and fungal infections but are also involved in the pathogenesis of autoimmune diseases. The retinoic acid-related orphan receptor (RORγt) is a key transcription factor involved in Th17 cell differentiation through direct transcriptional activation of interleukin 17(A) (IL-17). How RORγt itself is regulated remains unclear. Here, we report that p300, which has histone acetyltransferase (HAT) activity, interacts ...[more]

PMID: 26549310

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Project description: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 ?-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. ?-cell-specific Tph1-overexpressing transgenic rats and ?-cell-specific Tph1 knockout mice were constructed to evaluate the role of Tph1 in ?-cell function. The deacetylation of PKA in ?-cells by HDAC1 was investigated by adenoviral infection, immunoprecipitation, and western blot.Results: Inhibition of HDACs greatly potentiated pancreatic ?-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. ?-cell-specific Tph1-overexpressing transgenic rats exhibited improved glucose tolerance and amplified glucose-stimulated insulin secretion. On the contrary, ?-cell-specific Tph1 knockout mice displayed glucose intolerance and impaired insulin secretion with aging. Moreover, depletion of Tph1 in ?-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 ?-cell functional compensation by derepressing serotonin synthesis.

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Reciprocal regulation of ROR?t acetylation and function by p300 and HDAC1.

Publications

Reciprocal regulation of RORγt acetylation and function by p300 and HDAC1.

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