HSCARG negatively regulates the cellular antiviral RIG-I like receptor signaling pathway by inhibiting TRAF3 ubiquitination via recruiting OTUB1.
HSCARG negatively regulates the cellular antiviral RIG-I like receptor signaling pathway by inhibiting TRAF3 ubiquitination via recruiting OTUB1.
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HSCARG 通过招募 OTUB1 抑制 TRAF3 泛素化，负向调节细胞抗病毒 RIG-I 样受体信号通路。
DOI：
10.1371/journal.ppat.1004041
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发表时间：
2014-04
期刊：
影响因子：
6.7
通讯作者：
Zheng X
中科院分区：
文献类型：
--
作者：
Peng Y;Xu R;Zheng X
RIG-I样受体（RLRs）识别胞质病毒RNA并启动先天免疫；它们增加I型干扰素（IFN）的产生和一系列抗病毒基因的转录，以保护宿主生物。准确调控RLR通路对于避免过度免疫反应引起的组织损伤具有重要意义。HSCARG是新报道的NF-κB负调节因子。在这里，我们证明了HSCARG参与先天免疫。HSCARG以不依赖于NF-κB的方式抑制细胞抗病毒反应，而缺乏HSCARG则具有相反的作用。病毒感染后，HSCARG与肿瘤坏死受体相关因子3 （tumor necrosis receptor-associated factor 3, TRAF3）相互作用，通过促进OTUB1向TRAF3募集来抑制其泛素化。敲除HSCARG可减弱OTUB1对TRAF3的去泛素化作用，敲除OTUB1可消除HSCARG的作用。HSCARG在病毒感染后与Ikappa-B激酶epsilon （IKKε）相互作用，破坏TRAF3与IKKε的关联，进一步降低IKKε和干扰素反应因子3 （IRF3）的磷酸化，从而抑制IRF3的二聚化和核易位。此外，敲低TRAF3可抑制HSCARG对IFN-β转录的抑制作用，提示TRAF3是HSCARG下调RLR通路所必需的。本研究表明，HSCARG是一种负调节因子，可实现平衡的抗病毒先天免疫。先天免疫对宿主抵御病原体入侵至关重要，而干扰素（IFN）的产生是细胞抗病毒应答的核心，在大多数细胞类型中，干扰素的产生是由toll样受体（TLR）和RIG-I样受体（RLR）信号通路介导的。由于免疫反应的异常活动导致免疫缺陷或自身免疫性疾病，识别参与免疫平衡的调节因子尤为重要。越来越多的证据表明，泛素化在调节病毒触发的IFN产生中起着关键作用，以确保抗病毒反应得到适当调节。在这里，我们证明了HSCARG是精确控制抗病毒先天免疫的一种新的负调节因子。HSCARG通过OTUB1抑制TRAF3泛素化来抑制IFN-β的产生，导致下游IKKε的解耦和IRF3活性的损伤。作为TLR、RLR和非典型NF-κB通路的枢纽，TRAF3是一种非常通用的免疫调节剂。我们的研究揭示了TRAF3活性复杂调控的特异性和多样性实现机制，提示HSCARG是治疗炎症和自身免疫性疾病的潜在靶点。
RIG-I like receptors (RLRs) recognize cytosolic viral RNA and initiate innate immunity; they increase the production of type I interferon (IFN) and the transcription of a series of antiviral genes to protect the host organism. Accurate regulation of the RLR pathway is important for avoiding tissue injury induced by excessive immune response. HSCARG is a newly reported negative regulator of NF-κB. Here we demonstrated that HSCARG participates in innate immunity. HSCARG inhibited the cellular antiviral response in an NF-κB independent manner, whereas deficiency of HSCARG had an opposite effect. After viral infection, HSCARG interacted with tumor necrosis receptor-associated factor 3 (TRAF3) and inhibited its ubiquitination by promoting the recruitment of OTUB1 to TRAF3. Knockout of HSCARG attenuated the de-ubiquitination of TRAF3 by OTUB1, and knockdown of OTUB1 abolished the effect of HSCARG. HSCARG also interacted with Ikappa-B kinase epsilon (IKKε) after viral infection and impaired the association between TRAF3 and IKKε, which further decreased the phosphorylation of IKKε and interferon response factor 3 (IRF3), thus suppressed the dimerization and nuclear translocation of IRF3. Moreover, knockdown of TRAF3 dampened the inhibitory effect of IFN-β transcription by HSCARG, suggesting that TRAF3 is necessary for HSCARG to down-regulate RLR pathway. This study demonstrated that HSCARG is a negative regulator that enables balanced antiviral innate immunity. Innate immunity is critical for the host to defeat pathogen invasion, and the production of interferon (IFN) is the core of the cellular antiviral response, this is mediated by the Toll-like receptor (TLR) and RIG-I like receptor (RLR) signaling pathways in most cell types. As aberrant activity of the immune response leads to immune-deficiency or autoimmune disease, identification of the regulators involved in immune balance is particularly important. Accumulating evidence shows that ubiquitination plays a key role in regulating virus-triggered IFN production to assure that the antiviral response is modulated properly. Here, we demonstrated that HSCARG is a novel negative regulator in the precise control of antiviral innate immunity. HSCARG inhibited IFN-β production by suppressing TRAF3 ubiquitination with the help of OTUB1, leading to disassociation of downstream IKKε and impairment of IRF3 activity. As the pivot of the TLR, RLR, and non-canonical NF-κB pathways, TRAF3 is an extremely versatile immune regulator. Our study sheds light on the mechanism of specificity and diversity achievement in the complicated regulation of TRAF3 activity, suggesting that HSCARG is a potential target for the treatment of inflammatory and autoimmune diseases.
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