KAP1/TRIM28: An inhibitor of IRF5 function in inflammatory macrophages
KAP1/TRIM28: An inhibitor of IRF5 function in inflammatory macrophages
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DOI：
10.1016/j.imbio.2012.07.026
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发表时间：
2012-12-01
期刊：
影响因子：
2.8
通讯作者：
Udalova, I. A.
中科院分区：
文献类型：
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作者：
Eames, H. L.;Saliba, D. G.;Udalova, I. A.
IRF 5在诱导促炎细胞因子中起关键作用，有助于巨噬细胞的可塑性和极化为M1表型，并启动有效的T（H）1-T（H）17应答。为了更好地理解IRF 5转录作用的方式，我们通过亲和纯化结合质谱法对IRF 5相互作用伴侣进行了筛选，并将KAP 1/TRIM 28鉴定为IRF 5的新型蛋白质-蛋白质相互作用伴侣。KAP 1主要通过募集参与染色质沉默的复合物（如组蛋白脱乙酰酶和甲基转移酶）作为转录辅阻遏物。我们绘制了IRF 5的N-末端，包括其DNA结合结构域以及一个高度内在无序的区域，这对于IRF 5-KAP 1相互作用界面至关重要，并证明IRF 5也可以与甲基转移酶SETDB 1形成复合物。人M1巨噬细胞中KAP 1（TRIM 28）基因表达的敲低增强了IRF 5介导的TNF和其他M1巨噬细胞标志物的表达。这种作用可能与SETDB 1的甲基转移酶活性有关，如组蛋白3的赖氨酸9的三甲基化（H3 K9 me 3），在KAP 1敲低后，其在人TNF基因座的沉积减少。我们的研究进一步理解了TRIM和IRF蛋白家族之间复杂的分子相互作用，并强调了KAP 1的抑制特性与IRF 5介导的基因表达相关的作用。(C)2012 Elsevier GmbH. All rights reserved.
IRF5 plays a key role in the induction of pro-inflammatory cytokines, contributing to the plasticity and polarisation of macrophages to an M1 phenotype and initiation of a potent T(H)1-T(H)17 response. To better understand the means of IRF5 transcriptional action, we conducted a screen for IRF5-interacting partners by affinity purification coupled to mass spectrometry and identified KAP1/TRIM28 as a novel protein-protein interaction partner of IRF5. KAP1 acts as a transcriptional co-repressor, chiefly via recruitment of complexes involved in chromatin silencing, such as histone deacetylases and methyltransferases. We mapped the N-terminus of IRF5, encompassing its DNA-binding domain together with a highly intrinsically disordered region, as crucial for the IRF5-KAP1 interaction interface, and demonstrated that IRF5 can also form complexes with the methyltransferase SETDB1. Knockdown of KAP1 (TRIM28) gene expression in human M1 macrophages potentiated IRF5-mediated expression of TNF and other M1 macrophage markers. This effect may be linked to methyltransferase activity of SETDB1, such as trimethylation of lysine 9 of histone 3 (H3K9me3), deposition of which was decreased at the human TNF locus upon KAP1 knockdown. Our study furthers an understanding of the complex molecular interactions between the TRIM and IRF protein families, and highlights a role of the inhibitory properties of KAP1 in association with IRF5-mediated gene expression. (C) 2012 Elsevier GmbH. All rights reserved.