Melanoma differentiation-associated gene 5 is involved in the induction of stress granules and autophagy by protonophore CCCP
Melanoma differentiation-associated gene 5 is involved in the induction of stress granules and autophagy by protonophore CCCP
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DOI：
10.1515/hsz-2015-0195
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发表时间：
2016-01
影响因子：
3.7
通讯作者：
Feng Xu;Xiaobo Li;Peifen Zhang;Jun Xia;Yi Wang;Chao Yang;Huixin Gao;Shili Zhou;Ping Zhang
中科院分区：
文献类型：
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作者：
Feng Xu;Xiaobo Li;Peifen Zhang;Jun Xia;Yi Wang;Chao Yang;Huixin Gao;Shili Zhou;Ping Zhang
真核细胞已经进化出多种针对外界刺激的应激反应，如先天免疫、应激颗粒（SGs）的形成和自噬。我们之前证明了先天免疫适配器IFN-β启动子刺激因子1 （IPS-1）在dsrna诱导的SGs形成中起重要作用，表明SG形成与先天免疫之间存在联系。本研究进一步证实，黑色素瘤分化相关基因5 （MDA5）是一种先天免疫传感器，参与了羰基氰化物间氯苯腙（CCCP）（线粒体原体）诱导的SG形成。MDA5敲低对CCCP触发的真核翻译起始因子2α (eIF2α)磷酸化无显著影响，且MDA5自身未被募集到SGs中，提示MDA5在SG应答中的调控发生在eIF2α的下游。此外，MDA5或G3BP1的缺失导致cccp刺激细胞的自噬减少，这意味着MDA5对自噬的调节作用取决于其在SG形成中的作用。本研究揭示了先天免疫蛋白MDA5在原细胞CCCP触发的SG形成和自噬中的意想不到的作用，进一步支持了不同应激反应之间的相关性。
Abstract The eukaryotic cell has evolved a variety of stress responses against external stimuli, such as innate immunity, the formation of stress granules (SGs), and autophagy. We previously demonstrated that the innate immune adaptor IFN-β promoter stimulator 1 (IPS-1) plays an essential role in the formation of dsRNA-induced SGs, indicating a connection between SG formation and innate immunity. In this study, it was further demonstrated that melanoma differentiation-associated gene 5 (MDA5), an innate immune sensor, is involved in SG formation induced by carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial protonophore. MDA5 knockdown had no significant impact on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) triggered by CCCP, and MDA5 itself was not recruited to SGs, suggesting that the regulation of MDA5 in the SG response occurs downstream of eIF2α. Furthermore, the depletion of MDA5 or G3BP1 led to reduced autophagy in CCCP-stimulated cells, implying that the regulatory effect of MDA5 with respect to autophagy depends on its role in SG formation. This study uncovered an unexpected role of the innate immune protein MDA5 in SG formation and autophagy triggered by the protonophore CCCP, further supporting a correlation between different stress responses.