CSFV restricts necroptosis to sustain infection by inducing autophagy/mitophagy-targeted degradation of RIPK3.
CSFV restricts necroptosis to sustain infection by inducing autophagy/mitophagy-targeted degradation of RIPK3.
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CSFV通过诱导RIPK 3的自噬/线粒体自噬靶向降解来限制坏死性凋亡以维持感染。
DOI：
10.1128/spectrum.02758-23
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发表时间：
2024-01-11
影响因子：
3.7
通讯作者：
Chen, Jinding
中科院分区：
文献类型：
--
作者：
Wu, Keke;Li, Bingke;Zhang, Xiaoai;Fang, Yiqi;Zeng, Sen;Hu, Wenshuo;Liu, Xiaodi;Liu, Xueyi;Lu, Zhimin;Li, Xiaowen;Chen, Wenxian;Qin, Yuwei;Zhou, Bolun;Zou, Linke;Zhao, Feifan;Yi, Lin;Zhao, Mingqiu;Fan, Shuangqi;Chen, Jinding
作为宿主防御感染的重要组成部分，坏死性凋亡是一种新型的高度调节的细胞死亡模式，由含有受体相互作用蛋白激酶1（RIPK1）和RIPK3的信号复合物介导。猪瘟病毒（CSFV）感染猪后，淋巴细胞减少和免疫功能低下是其典型的临床特征。在这里，我们提供了第一个证据参与坏死性凋亡的T淋巴细胞在体内感染猪瘟病毒的猪的脾脏和外周血中的坏死。然而，对于一些具有非细胞病变效应的病毒，包括CSFV，平衡宿主对感染的防御是正确的。在体外，CSFV在感染后期诱导自噬明显限制了坏死性凋亡。机制研究表明，猪瘟病毒NS4A蛋白可促进含三联模体25的表达，协同诱导线粒体自噬的发生，靶向RIPK3的自噬降解，阻断坏死性凋亡的发生，实现病毒的持续感染。有趣的是，我们发现RIPK3能够特异性地定位于线粒体外膜，并且自噬受体NDP 52最有可能参与CSFV感染期间RIPK3的自噬降解。我们的研究结果提供了证据支持，CSFV诱导的自噬途径在抵消宿主细胞坏死中起着重要作用，丰富了我们对可能破坏和逃避坏死性凋亡这种宿主防御的病原体的认识，并为理解CSFV感染期间T淋巴细胞耗竭和免疫抑制的机制提供了新的思路。猪瘟病毒感染猪后会引起持续高热、出血坏死性多器官炎症和高死亡率，严重威胁全球养猪业。细胞死亡是宿主抵抗病原体入侵的一种基本免疫反应，而淋巴细胞减少是CSFV感染急性期最典型的临床特征，影响宿主最初的抗病毒免疫。作为一种“古老”的病毒，猪瘟病毒经过长期的遗传进化，已经进化出逃避宿主免疫反应的机制。在这里，我们表明，坏死性凋亡是一个限制性的CSFV感染的宿主因素，CSFV诱导的自噬可以颠覆这种宿主防御机制，以促进其持续复制。我们的研究结果揭示了细胞死亡过程中坏死性凋亡和自噬之间的复杂联系，提供了支持CSFV在抵消宿主细胞坏死中的重要作用的证据，并丰富了我们对可能破坏和逃避这种宿主防御的病原体的认识。
As an essential component of host defense against infection, necroptosis is a novel highly regulated mode of cell death that is mediated by signaling complexes containing receptor-interacting protein kinase 1 (RIPK1) and RIPK3. Lymphocyte depletion and immunosuppression are typical clinical features of pigs infected with classical swine fever virus (CSFV). Here, we provide the first evidence for the involvement of necroptosis in the necrosis of T lymphocytes in the spleen and peripheral blood of pigs infected in vivo with CSFV. However, it is true for some viruses with non-cytopathic effects, including CSFV, to balance host defense against infection. In vitro, the induction of autophagy by CSFV at a later stage of infection clearly restricts necroptosis. Mechanistic studies revealed that CSFV NS4A protein promoted tripartite motif-containing 25 expression, synergistically induced the occurrence of mitophagy, targeted the autophagic degradation of RIPK3 to block the progression of necroptosis occurrence, and achieved persistent viral infection. Interestingly, we found that RIPK3 was able to specifically localize at the outer mitochondrial membrane, and the autophagy receptor NDP52 was most likely involved in the autophagic degradation of RIPK3 during CSFV infection. Our findings provide evidence supporting that the CSFV-induced autophagy pathway plays an important role in counteracting host cell necrosis, enriching our knowledge of pathogens that may subvert and evade necroptosis this host defense, and shedding new light on understanding the mechanisms of T lymphocyte exhaustion and immunosuppression during CSFV infection. CSFV infection in pigs causes persistent high fever, hemorrhagic necrotizing multi-organ inflammation, and high mortality, which seriously threatens the global swine industry. Cell death is an essential immune response of the host against pathogen invasion, and lymphopenia is the most typical clinical feature in the acute phase of CSFV infection, which affects the initial host antiviral immunity. As an “old” virus, CSFV has evolved mechanisms to evade host immune response after a long genetic evolution. Here, we show that necroptosis is a limiting host factor for CSFV infection and that CSFV-induced autophagy can subvert this host defense mechanism to promote its sustained replication. Our findings reveal a complex link between necroptosis and autophagy in the process of cell death, provide evidence supporting the important role for CSFV in counteracting host cell necrosis, and enrich our knowledge of pathogens that may subvert and evade this host defense.
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DOI：
10.3390/v9070171
发表时间：
2017-07-05
期刊：
Viruses
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