裂谷热病毒（RVFV）是一种高致病性的蚊媒人畜共患病毒，其感染会引发严重的炎症发病机制，但炎症激活的潜在机制目前尚不清楚。在这里，我们报道了RVFV的非结构蛋白NSs触发线粒体损伤，激活NLRP3炎性体，导致病毒在体内发病。研究发现，NSs 的宿主转录抑制作用会导致髓样细胞白血病-1 (MCL-1) 快速下调，MCL-1 是 Bcl-2（B 细胞淋巴瘤蛋白 2）蛋白家族的促生存成员。 MCL-1 下调导致线粒体中的 BAK 激活，从而触发 mtROS 产生并将氧化线粒体 DNA (ox-mtDNA) 释放到细胞质中。细胞溶质 ox-mtDNA 结合并激活 NLRP3 炎性体，在 RVFV 感染细胞中触发 NLRP3-GSDMD 焦亡。诱导转录抑制受到损害的 NSs 突变病毒 (RVFV-NSsRM) 不会触发 MCL-1 下调，也不会触发 NLRP3-GSDMD 焦亡。 Nlrp3-/-小鼠模型的RVFV感染表明，RVFV触发的NLRP3焦亡有助于RVFV炎症发病机制和体内致命感染。 RVFV-NSsRM 突变病毒感染同样显示出炎症发病机制的减轻和死亡率的降低。总而言之，这些结果揭示了毒力因子通过诱导宿主转录抑制来激活线粒体 MCL-1-BAK 轴以触发 NLRP3 依赖性炎症发病机制的机制。版权所有：© 2024guan 等人。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

Infection of Rift Valley fever virus (RVFV), a highly pathogenic mosquito-borne zoonotic virus, triggers severe inflammatory pathogenesis but the underlying mechanism of inflammation activation is currently unclear. Here, we report that the non-structural protein NSs of RVFV triggers mitochondrial damage to activate the NLRP3 inflammasome leading to viral pathogenesis in vivo. It is found that the host transcription inhibition effect of NSs causes rapid down-regulation of myeloid cell leukemia-1(MCL-1), a pro-survival member of the Bcl-2 (B-cell lymphoma protein 2) protein family. MCL-1 down-regulation led to BAK activation in the mitochondria, which triggered mtROS production and release of oxidized mitochondrial DNA (ox-mtDNA) into the cytosol. Cytosolic ox-mtDNA binds and activates the NLRP3 inflammasome triggering NLRP3-GSDMD pyroptosis in RVFV infected cells. A NSs mutant virus (RVFV-NSsRM) that is compromised in inducing transcription inhibition did not trigger MCL-1 down-regulation nor NLRP3-GSDMD pyroptosis. RVFV infection of the Nlrp3-/- mouse model demonstrated that the RVFV-triggered NLRP3 pyroptosis contributed to RVFV inflammatory pathogenesis and fatal infection in vivo. Infection with the RVFV-NSsRM mutant virus similarly showed alleviated inflammatory pathogenesis and reduced fatality rate. Taken together, these results revealed a mechanism by which a virulence factor activates the mitochondrial MCL-1-BAK axis through inducing host transcription inhibition to trigger NLRP3-dependent inflammatory pathogenesis.Copyright: © 2024 Guan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.