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首页> 外文期刊>Molecular and Cellular Biology >The COP9 Signalosome Interacts with and Regulates Interferon Regulatory Factor 5 Protein Stability
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The COP9 Signalosome Interacts with and Regulates Interferon Regulatory Factor 5 Protein Stability

机译：COP9 Signalosome与干扰素调节因子5蛋白质相互作用并调节其稳定性。

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The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization. Tight regulation of IRF5 is thus warranted for an efficient response toward extracellular stressors and for limiting autoimmune and inflammatory responses. Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with IRF5 and promotes its protein stability. The constitutive CSN/IRF5 interaction was identified using proteomics and confirmed by endogenous immunoprecipitations. The CSN/IRF5 interaction occurred on the carboxyl and amino termini of IRF5; a single internal deletion from amino acids 455 to 466 (Δ455-466) was found to significantly reduce IRF5 protein stability. CSN subunit 3 (CSN3) was identified as a direct interacting partner of IRF5, and knockdown of this subunit with small interfering RNAs resulted in enhanced degradation. Degradation was further augmented by knockdown of CSN1 and CSN3 together. The ubiquitin E1 inhibitor UBEI-41 or the proteasome inhibitor MG132 prevented IRF5 degradation, supporting the idea that its stability is regulated by the ubiquitin-proteasome system. Importantly, activation of IRF5 by the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in enhanced degradation via loss of the CSN/IRF5 interaction. This study defines CSN to be a new interacting partner of IRF5 that controls its stability.
机译：转录因子干扰素调节因子5（IRF5）在调节宿主抵抗细胞外病原体的免疫力，DNA损伤诱导的细胞凋亡，死亡受体信号传导和巨噬细胞极化中起着至关重要的作用。因此，为了对细胞外应激源进行有效应答并限制自身免疫和炎症应答，有必要对IRF5进行严格调节。在这里我们报告说，COP9信号小体（CSN），各种细胞和发育过程的一般调节剂，与IRF5组成型缔合，并促进其蛋白质稳定性。使用蛋白质组学鉴定本构CSN / IRF5相互作用，并通过内源性免疫沉淀确认。 CSN / IRF5相互作用发生在IRF5的羧基和氨基末端。发现从氨基酸455至466的单个内部缺失（Δ455-466）显着降低了IRF5蛋白的稳定性。 CSN亚基3（CSN3）被确定为IRF5的直接相互作用伙伴，并且用小的干扰RNA敲除该亚基导致降解增强。通过一起击倒CSN1和CSN3，降解进一步加剧。泛素E1抑制剂UBEI-41或蛋白酶体抑制剂MG132阻止了IRF5降解，支持了其稳定性受泛素-蛋白酶体系统调节的观点。重要的是，死亡受体配体肿瘤坏死因子相关的凋亡诱导配体（TRAIL）对IRF5的激活通过CSN / IRF5相互作用的丧失导致降解增强。这项研究将CSN定义为控制其稳定性的IRF5的新交互伙伴。

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