A human-specific motif facilitates CARD8 inflammasome activation after HIV-1 infection.
A human-specific motif facilitates CARD8 inflammasome activation after HIV-1 infection.
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HIV-1 感染后，人类特异性基序促进 CARD8 炎性体激活。
DOI：
10.7554/elife.84108
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发表时间：
2023-07-07
期刊：
影响因子：
7.7
通讯作者：
Mitchell PS
中科院分区：
文献类型：
--
作者：
Kulsuptrakul J;Turcotte EA;Emerman M;Mitchell PS
炎性小体是细胞溶质先天免疫复合物，其在检测到多种病原体相关的线索时组装，并在宿主防御和炎症发病机制中发挥关键作用。在这里，我们发现人类炎性小体形成传感器CARD8通过HIV蛋白酶（HIV-1PR）对CARD8 N-末端的位点特异性切割来感知HIV-1感染。CARD8的HIV-1PR裂解诱导热变性细胞死亡和促炎细胞因子从感染细胞的释放，这是在病毒感染之前由Toll样受体刺激调节的过程。在急性感染的细胞中，CARD8可以感知从头翻译的HIV-1PR和从进入的病毒体释放的包装HIV-1PR的活性。此外，我们的进化分析表明，人类CARD8中的HIV-1PR切割位点是在黑猩猩和人类分化之后出现的。虽然黑猩猩CARD8不识别来自HIV或来自黑猩猩的猿免疫缺陷病毒（SIVcpz）的蛋白酶，但SIVcpz确实切割人类CARD8，这表明SIVcpz在跨物种传播到人类之前准备激活人类CARD8炎性小体。我们的研究结果表明CARD8炎性小体激活在响应人类慢病毒感染中的独特作用。
Inflammasomes are cytosolic innate immune complexes that assemble upon detection of diverse pathogen-associated cues and play a critical role in host defense and inflammatory pathogenesis. Here, we find that the human inflammasome-forming sensor CARD8 senses HIV-1 infection via site-specific cleavage of the CARD8 N-terminus by the HIV protease (HIV-1PR). HIV-1PR cleavage of CARD8 induces pyroptotic cell death and the release of pro-inflammatory cytokines from infected cells, processes regulated by Toll-like receptor stimulation prior to viral infection. In acutely infected cells, CARD8 senses the activity of both de novo translated HIV-1PR and packaged HIV-1PR that is released from the incoming virion. Moreover, our evolutionary analyses reveal that the HIV-1PR cleavage site in human CARD8 arose after the divergence of chimpanzees and humans. Although chimpanzee CARD8 does not recognize proteases from HIV or simian immunodeficiency viruses from chimpanzees (SIVcpz), SIVcpz does cleave human CARD8, suggesting that SIVcpz was poised to activate the human CARD8 inflammasome prior to its cross-species transmission into humans. Our findings suggest a unique role for CARD8 inflammasome activation in response to lentiviral infection of humans.
HIV蛋白酶：防止免疫检测的后期行动。
影响因子：
39.3
作者：
Sparrer KMJ;Kirchhoff F
通讯作者：
Kirchhoff F