The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling
The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling
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DOI：
10.1126/science.aaw4144
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发表时间：
2019-07-05
期刊：
影响因子：
56.9
通讯作者：
Girardin, Stephen E.
中科院分区：
文献类型：
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作者：
Abdel-Nour, Mena;Carneiro, Leticia A. M.;Girardin, Stephen E.
多个胞质先天感受器激活后形成大的信号体，但这种组装需要严格调控，以避免错误折叠的聚集体积累。我们发现，eIF2a激酶血红素调节抑制物(HRI)通过需要真核细胞启动因子2α(eIF2α)、转录因子ATF4和热休克蛋白HSPB8的过程来控制NOD1信号体的折叠和激活。HRI/eIF2α信号轴对于天然免疫介质NOD2、MAVS和TRIF的下游信号也是必不可少的，但对于依赖MyD88或STIN的通路来说是必不可少的。此外，微丝形成的α-突触核蛋白激活了HRI依赖的反应，这表明HRI途径可能限制了有毒低聚物的形成。我们认为，HRI、eIF2α和HSPB8通过大分子平台定义了一种新的胞浆未折叠蛋白反应(CUPR)，在功能上与内质网UPR的PERK/eIF2α/HSPA5轴同源，对于优化天然免疫信号是必不可少的。
Multiple cytosolic innate sensors form large signalosomes after activation, but this assembly needs to be tightly regulated to avoid accumulation of misfolded aggregates. We found that the eIF2a kinase heme-regulated inhibitor (HRI) controls NOD1 signalosome folding and activation through a process requiring eukaryotic initiation factor 2 alpha (eIF2 alpha), the transcription factor ATF4, and the heat shock protein HSPB8. The HRI/eIF2 alpha signaling axis was also essential for signaling downstream of the innate immune mediators NOD2, MAVS, and TRIF but dispensable for pathways dependent on MyD88 or STING. Moreover, filament-forming a-synuclein activated HRI-dependent responses, which suggests that the HRI pathway may restrict toxic oligomer formation. We propose that HRI, eIF2 alpha, and HSPB8 define a novel cytosolic unfolded protein response (cUPR) essential for optimal innate immune signaling by large molecular platforms, functionally homologous to the PERK/eIF2 alpha/HSPA5 axis of the endoplasmic reticulum UPR.