Virus-mediated inactivation of anti-apoptotic Bcl-2 family members promotes Gasdermin-E-dependent pyroptosis in barrier epithelial cells.
Virus-mediated inactivation of anti-apoptotic Bcl-2 family members promotes Gasdermin-E-dependent pyroptosis in barrier epithelial cells.
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DOI：
10.1016/j.immuni.2021.04.012
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发表时间：
2021-07-13
期刊：
影响因子：
32.4
通讯作者：
Kagan JC
中科院分区：
文献类型：
--
作者：
Orzalli MH;Prochera A;Payne L;Smith A;Garlick JA;Kagan JC
两套先天免疫蛋白可以检测病原体。模式识别受体(PRRs)结合微生物产物，而Guard蛋白通过监测细胞内的稳态过程来检测毒力因子的活性。虽然PRR因其在许多类型的感染中的作用而广为人知，但保卫蛋白在大多数感染环境中的作用仍然知之甚少。在这里，我们证明了在病毒感染过程中抑制蛋白质合成被认为是一种毒力策略，并引发了人角质形成细胞的角质形成下垂。我们鉴定了Bcl2家族成员Mcl-1和Bclxl是翻译关闭的感受者。病毒或化学诱导的翻译抑制导致Mcl-1耗竭和Bclxl失活，导致线粒体损伤，caspase3依赖的Gasdermin E裂解，IL-1α的释放。阻断这一途径增强了人体皮肤器官模型中的病毒复制。因此，Mcl-1和Bclxl可以作为屏障上皮细胞内的保护蛋白，有助于抗病毒防御。模式识别受体因其在抗病毒防御中的作用而广为人知，但保卫蛋白在感知病毒感染方面的作用尚不清楚。Orzalli等人揭示了Bcl2家族成员MCL-1和BCL-XL作为病毒介导的蛋白质合成抑制的保护蛋白，并在失活时触发下垂。
Two sets of innate immune proteins detect pathogens. Pattern recognition receptors (PRRs) bind microbial products, whereas guard proteins detect virulence factor activities by the surveillance of homeostatic processes within cells. While PRRs are well-known for their roles in many types of infections, the role of guard proteins in most infectious contexts remains less understood. Here, we demonstrated that inhibition of protein synthesis during viral infection is sensed as a virulence strategy and initiates pyroptosis in human keratinocytes. We identified the Bcl-2 family members Mcl-1 and Bcl-xL as sensors of translation shutdown. Virus or chemical-induced translation inhibition resulted in Mcl-1 depletion and inactivation of Bcl-xL, leading to mitochondria damage, caspase-3 dependent cleavage of Gasdermin E, and release of IL-1α. Blocking this pathway enhanced virus replication in an organoid model of human skin. Thus, Mcl-1 and Bcl-xL can act as guard proteins within barrier epithelia and contribute to antiviral defense. Pattern recognition receptors are well-known for their roles in antiviral defense, but the role of guard proteins in sensing viral infection is less clear. Orzalli et al reveal that the Bcl-2 family members MCL-1 and BCL-xL act as guard proteins of virus-mediated protein synthesis inhibition and trigger pyroptosis upon inactivation.
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影响因子：
28.3
作者：
通讯作者：
--
DOI：
10.1158/1078-0432.ccr-12-3066
发表时间：
2013-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cheng Z;Gong Y;Ma Y;Lu K;Lu X;Pierce LA;Thompson RC;Muller S;Knapp S;Wang J
通讯作者：
Wang J
形成孔的蛋白质加油D可以调节白细胞介素-1的巨噬细胞分泌。
影响因子：
32.4
作者：
Evavold CL;Ruan J;Tan Y;Xia S;Wu H;Kagan JC
通讯作者：
Kagan JC
影响因子：
4.8
作者：
Connor, JH;Lyles, DS
通讯作者：
Lyles, DS
影响因子：
15.9
作者：
Elgendy, Mohamed;Abdel-Aziz, Amal Kamal;Minucci, Saverio
通讯作者：
Minucci, Saverio