Pattern Recognition Receptors of Nucleic Acids Can Cause Sublethal Activation of the Mitochondrial Apoptosis Pathway during Viral Infection
Pattern Recognition Receptors of Nucleic Acids Can Cause Sublethal Activation of the Mitochondrial Apoptosis Pathway during Viral Infection
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DOI：
10.1128/jvi.01212-22
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发表时间：
2022-09
影响因子：
5.4
通讯作者：
Sylwia Gradzka-Boberda;I. Gentle;G. Häcker
中科院分区：
文献类型：
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作者：
Sylwia Gradzka-Boberda;I. Gentle;G. Häcker
线粒体凋亡装置的贡献，在没有细胞死亡的情况下，非专业免疫细胞对病毒的反应被认为是作为一个广泛的警报系统的感染细胞发挥作用：细胞凋亡系统可以被激活的许多上游信号，因此可以作为一个中央协调员的病毒识别。PRR的促凋亡活性已经在多种情况下被记录，但是这种活性似乎太低而没有意义，并且这种活性的生理意义并不立即明显。摘要线粒体凋亡途径具有杀死细胞的功能，但最近的研究表明，这一途径也可以被激活到亚致死水平，在那里可以观察到信号转导，但细胞存活。有趣的是，这种信号传导已被证明有助于上皮细胞在感染多种药物后的炎症活性。这表明微生物识别可以在线粒体凋亡途径中产生亚致死活性。由于这种识别是通过模式识别受体（PRR）实现的，因此也意味着PRR信号与线粒体凋亡装置有关。我们在这里测试这一假设在感染上皮细胞与修改后的安卡拉牛痘病毒（MVA）。MVA识别是通过对核酸特异性的受体实现的，我们提出的证据表明，Toll样受体3（TLR 3）、RIG-I/MDA 5和环GMP-AMP合酶（cGAS）/干扰素基因刺激因子（STING）这三种受体参与了这种信号传导。当被特异性配体直接刺激时，这三种受体都能触发亚致死性凋亡信号。在MVA感染期间，X连锁IAP（XIAP）缺陷细胞中的亚致死凋亡信号被揭开，观察到凋亡诱导。三种信号传导衔接子TRIF、MAVS和STING中的任何一种的缺失都降低了DNA损伤反应，这是亚致死细胞凋亡信号的敏感量度。我们的研究结果表明，PRR通过线粒体发出信号，在线粒体中它们通过BCL-2家族产生亚致死信号，这可能有助于对传染性病原体的反应。重要性线粒体凋亡装置的贡献，在没有细胞死亡的情况下，非专业免疫细胞对病毒的反应被认为是作为一个广泛的警报系统的感染细胞的作用：凋亡系统可以被激活的许多上游信号，因此可以作为一个中央协调员的病毒识别。PRR的促凋亡活性已经在多种情况下被记录，但是这种活性似乎太低而没有意义，并且这种活性的生理意义并不立即明显。这项工作提出了另一种解释，PRRs不具有诱导凋亡的主要功能，但在凋亡系统中触发亚致死信号。最近的一些研究表明，线粒体有助于细胞反应，这一途径可能是触发早期宿主反应的一种方式。
A contribution of the mitochondrial apoptosis apparatus, in the absence of cell death, to the reaction of nonprofessional immune cells to viruses is suggested to play a role as a broad alert system of an infected cell: the apoptosis system can be activated by many upstream signals and could therefore act as a central coordinator of viral recognition. The proapoptotic activity of PRRs has been documented in multiple situations, but this activity seems too low to be meaningful, and a physiological significance of such activity is not immediately obvious. ABSTRACT The mitochondrial apoptosis pathway has the function to kill the cell, but recent work shows that this pathway can also be activated to a sublethal level, where signal transduction can be observed but the cell survives. Intriguingly, this signaling has been shown to contribute to inflammatory activity of epithelial cells upon infection with numerous agents. This suggests that microbial recognition can generate sublethal activity in the mitochondrial apoptosis pathway. Because this recognition is achieved by pattern recognition receptors (PRRs), it also implies that PRR signals are linked to the mitochondrial apoptosis apparatus. We here test this hypothesis during infection of epithelial cells with modified vaccinia virus Ankara (MVA). MVA recognition is achieved through receptors specific for nucleic acids, and we present evidence that the three receptors, Toll-like receptor 3 (TLR3), RIG-I/MDA5, and cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING), are involved in this signaling. When stimulated directly by specific ligands, all three receptors could trigger sublethal apoptosis signals. During infection with MVA, sublethal apoptosis signals were unmasked in X-linked IAP (XIAP)-deficient cells, where apoptosis induction was observed. Deletion of any of the three signaling adapters, TRIF, MAVS, and STING, reduced the DNA damage response, a sensitive measure of sublethal apoptosis signals. Our results suggest that PRRs signal via mitochondria, where they generate sublethal signals through the BCL-2-family, which may contribute to the response to infectious agents. IMPORTANCE A contribution of the mitochondrial apoptosis apparatus, in the absence of cell death, to the reaction of nonprofessional immune cells to viruses is suggested to play a role as a broad alert system of an infected cell: the apoptosis system can be activated by many upstream signals and could therefore act as a central coordinator of viral recognition. The proapoptotic activity of PRRs has been documented in multiple situations, but this activity seems too low to be meaningful, and a physiological significance of such activity is not immediately obvious. This work suggests the alternative interpretation that PRRs do not have the primary function to induce apoptosis but to trigger sublethal signals in the apoptosis system. A number of lines of recent research suggest that mitochondria contribute to cellular reactions, and this pathway may be a way of triggering an early host response.