DNAJB1/HSP40 Suppresses Melanoma Differentiation-Associated Gene 5-Mitochondrial Antiviral Signaling Protein Function in Conjunction with HSP70
DNAJB1/HSP40 Suppresses Melanoma Differentiation-Associated Gene 5-Mitochondrial Antiviral Signaling Protein Function in Conjunction with HSP70
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DOI：
10.1159/000480740
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发表时间：
2018-01-01
影响因子：
5.3
通讯作者：
Seya, Tsukasa
中科院分区：
文献类型：
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作者：
Takashima, Ken;Oshiumi, Hiroyuki;Seya, Tsukasa
黑色素瘤分化相关基因5（MDA 5）是一种模式识别受体，可识别细胞质病毒双链RNA（dsRNA）并启动快速的先天性抗病毒反应。MDA 5与dsRNA形成一个沿着的多聚体，导致寡聚化，进而激活衔接蛋白线粒体抗病毒信号蛋白（MAVS），为诱导I型干扰素（IFN）和促炎细胞因子提供信号平台。MDA 5的构象转换引起抗病毒防御，但MDA 5-MAVS通路的过度激活可能导致自身免疫性疾病。MDA 5激活的调节机制在很大程度上仍然未知。利用酵母双杂交技术，我们鉴定了热休克蛋白40（HSP 40）家族成员DNAJB 1为MDA 5结合蛋白。HSP 40通常与HSP 70协同作用。我们发现，dsRNA刺激与生理条件上调DNAJB 1和HSP 70的表达水平，然后蛋白质被耦合和易位到应激颗粒，在那里MDA 5遇到dsRNA。DNAJB 1破坏MDA 5多聚体的形成，导致I型IFN诱导的抑制。内源性DNAJB 1的破坏增加了MDA 5和MAVS介导的IFN启动子激活，并使细胞具有病毒抗性。HSP 70抑制剂也能增强MDA 5和MAVS的IFN诱导功能。这些结果表明DNAJB 1-HSP 70复合物通过与MDA 5/MAVS相互作用而发挥RNA传感的天然维持功能。(C)2017 S. Karger AG，巴塞尔
Melanoma differentiation-associated gene 5 (MDA5) is a pattern recognition receptor that recognizes cytoplasmic viral double-stranded RNA (dsRNA) and initiates rapid innate antiviral responses. MDA5 forms a filament-like multimer along the dsRNA leading to oligomerization, which in turn activates the adaptor protein mitochondrial antiviral signaling protein (MAVS) to provide a signal platform for the induction of type I interferon (IFN) and proinflammatory cytokines. The conformational switch of MDA5 causes antiviral defense, but excessive activation of the MDA5-MAVS pathway may result in autoimmune diseases. The regulatory mechanisms of MDA5 activation remain largely unknown. By yeast 2-hybrid, we identified DNAJB1, a member of the HSP40 (heat shock protein 40) family, as an MDA5-binding protein. HSP40s usually cowork with HSP70s. We found that dsRNA stimulation with physiological conditions upregulated the expression levels of DNAJB1 and HSP70; then the proteins were coupled and translocated into the stress granules, where MDA5 encounters dsRNA. DNAJB1 disrupted MDA5 multimer formation, resulting in the suppression of type I IFN induction. The disruption of endogenous DNAJB1 increased MDA5- and MAVS-mediated IFN promoter activation and rendered cells virus resistant. HSP70 inhibitor also enhanced the IFN-inducing function of MDA5 and MAVS. These results suggest that the DNAJB1-HSP70 complex functions for the natural maintenance of RNA sensing by interacting with MDA5/MAVS. (C) 2017 S. Karger AG, Basel