Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response.
Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response.
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DOI：
10.1126/sciadv.1501257
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发表时间：
2016-02
期刊：
影响因子：
13.6
通讯作者：
La Thangue NB
中科院分区：
文献类型：
--
作者：
Ghari F;Quirke AM;Munro S;Kawalkowska J;Picaud S;McGouran J;Subramanian V;Muth A;Williams R;Kessler B;Thompson PR;Fillipakopoulos P;Knapp S;Venables PJ;La Thangue NB
PAD 4介导的E2 F-1转录因子的瓜氨酸化及其与乙酰化的相互作用影响炎症基因表达肽基精氨酸脱亚胺酶4（PAD 4）是将精氨酸残基转化为瓜氨酸的核酶。虽然越来越多地参与炎症性疾病和癌症，但PAD 4的作用机制及其功能相关途径仍不清楚。E2 F转录因子是在细胞增殖和不同细胞命运期间协调基因表达的主调节因子家族。我们发现E2 F-1在炎症细胞中被PAD 4瓜氨酸化。瓜氨酸E2 F-1协助其染色质缔合，特别是粒细胞中的细胞因子基因。从机制上讲，瓜氨酸增强BET（布罗莫结构域和末端外结构域）家族布罗莫结构域阅读器BRD 4（含布罗莫结构域蛋白4）与E2 F-1中乙酰化结构域的结合，并且PAD 4和BRD 4与E2 F-1在细胞因子基因启动子上共存。因此，PAD 4和BRD 4的组合抑制破坏染色质结合的复合物并抑制细胞因子基因表达。在鼠胶原诱导的关节炎模型中，在PAD 4和BRD 4的小分子抑制后，炎性细胞中染色质结合的E2 F-1和随后的细胞因子表达减少，并且联合治疗在预防疾病进展方面具有临床有效性。我们的研究结果揭示了一种新的基于转录的机制，该机制介导了PAD 4的炎症效应，并建立了瓜氨酸和乙酰化在控制E2 F-1中的相互作用，作为驱动炎症基因表达的调控界面。
PAD4-mediated citrullination of E2F-1 transcription factor and its interplay with acetylation affects inflammatory gene expression. Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains unclear. E2F transcription factors are a family of master regulators that coordinate gene expression during cellular proliferation and diverse cell fates. We show that E2F-1 is citrullinated by PAD4 in inflammatory cells. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells. Mechanistically, citrullination augments binding of the BET (bromodomain and extra-terminal domain) family bromodomain reader BRD4 (bromodomain-containing protein 4) to an acetylated domain in E2F-1, and PAD4 and BRD4 coexist with E2F-1 on cytokine gene promoters. Accordingly, the combined inhibition of PAD4 and BRD4 disrupts the chromatin-bound complex and suppresses cytokine gene expression. In the murine collagen-induced arthritis model, chromatin-bound E2F-1 in inflammatory cells and consequent cytokine expression are diminished upon small-molecule inhibition of PAD4 and BRD4, and the combined treatment is clinically efficacious in preventing disease progression. Our results shed light on a new transcription-based mechanism that mediates the inflammatory effect of PAD4 and establish the interplay between citrullination and acetylation in the control of E2F-1 as a regulatory interface for driving inflammatory gene expression.