Human Cytomegalovirus-Induced Autophagy Prevents Necroptosis of Infected Monocytes
Human Cytomegalovirus-Induced Autophagy Prevents Necroptosis of Infected Monocytes
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DOI：
10.1128/jvi.01022-20
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发表时间：
2020-11-01
影响因子：
5.4
通讯作者：
Chan, Gary C.
中科院分区：
文献类型：
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作者：
Altman, Aaron M.;Miller, Michael J.;Chan, Gary C.
人类巨细胞病毒（HCMV）病毒传播策略的关键是诱导单核细胞存活，其中单核细胞通常是短命细胞。自噬是一种细胞过程，可以在应激时保持细胞稳态并促进细胞存活。我们发现 HCMV 在受感染的单核细胞内迅速诱导自噬。 HCMV 感染过程中早期诱导自噬对于 HCMV 感染的单核细胞的生存显然是必需的，因为自噬体形成的抑制会导致感染细胞的细胞死亡，但对未感染的单核细胞的生存能力没有影响。半胱天冬酶的抑制不足以挽救自噬抑制的感染单核细胞的细胞活力，这表明自噬并不能保护细胞免于凋亡。因此，我们发现 HCMV 阻断了 caspase 8 的激活，而这种激活在自噬抑制剂存在的情况下得以维持。坏死性凋亡是细胞凋亡受阻时触发的另一种细胞死亡形式，依赖于 MLKL 的 RIPK3 磷酸化。虽然我们发现HCMV在感染后激活RIP3K，但MLKL并未激活。然而，自噬的抑制消除了 MLKL RIPK3 磷酸化的阻断，表明自噬正在保护受感染的单核细胞免于坏死性凋亡。事实上，当 MLKL 和 RIPK3 被抑制时，自噬抑制的 HCMV 感染的单核细胞的存活得以挽救。总而言之，这些数据表明 HCMV 诱导自噬以防止坏死性细胞死亡，从而确保受感染单核细胞的存活，从而促进病毒在宿主内传播。 重要性 人类巨细胞病毒 (HCMV) 感染在世界各地流行，血清阳性率为 40% 至 100%，具体取决于地理位置。 HCMV 感染通常无症状，但可在免疫功能低下的个体中引起严重的炎症器官疾病。由 HCMV 引起的一系列器官疾病与单核细胞介导的病毒系统性传播直接相关。单核细胞自然会经历细胞凋亡，HCMV 会迅速阻断细胞凋亡，以确保受感染的单核细胞存活并传播到不同的器官部位。在这项工作中，我们证明受感染的单核细胞也会启动坏死性凋亡，作为响应 HCMV 破坏细胞凋亡的“陷阱门”死亡途径。然后，HCMV 激活细胞自噬作为防止坏死性凋亡执行的对策，从而促进受感染单核细胞的持续存活。阐明 HCMV 刺激单核细胞存活的机制是开发防止受感染单核细胞扩散的新型抗 HCMV 药物的重要一步。
Key to the viral dissemination strategy of human cytomegalovirus (HCMV) is the induction of monocyte survival, where monocytes are normally short-lived cells. Autophagy is a cellular process that preserves cellular homeostasis and promotes cellular survival during times of stress. We found that HCMV rapidly induced autophagy within infected monocytes. The early induction of autophagy during HCMV infection was distinctly required for the survival of HCMV-infected monocytes, as repression of autophagosome formation led to cellular death of infected cells but had no effect on the viability of uninfected monocytes. The inhibition of caspases was insufficient to rescue cell viability of autophagy-repressed infected monocytes, suggesting that autophagy was not protecting cells from apoptosis. Accordingly, we found that HCMV blocked the activation of caspase 8, which was maintained in the presence of autophagy inhibitors. Necroptosis is an alternative form of cell death triggered when apoptosis is impeded and is dependent on RIPK3 phosphorylation of MLKL. Although we found that HCMV activated RIP3K upon infection, MLKL was not activated. However, inhibition of autophagy removed the block in RIPK3 phosphorylation of MLKL, suggesting that autophagy was protecting infected monocytes from undergoing necroptosis. Indeed, survival of autophagyinhibited HCMV-infected monocytes was rescued when MLKL and RIPK3 were suppressed. Taken together, these data indicate that HCMV induces autophagy to prevent necroptotic cell death in order to ensure the survival of infected monocytes and thus facilitate viral dissemination within the host.IMPORTANCE Human cytomegalovirus (HCMV) infection is endemic throughout the world, with a seroprevalence of 40 to 100% depending on geographic location. HCMV infection is generally asymptomatic, but can cause severe inflammatory organ diseases in immunocompromised individuals. The broad array of organ diseases caused by HCMV is directly linked to the systematic spread of the virus mediated by monocytes. Monocytes are naturally programmed to undergo apoptosis, which is rapidly blocked by HCMV to ensure the survival and dissemination of infected monocytes to different organ sites. In this work, we demonstrate infected monocytes also initiate necroptosis as a "trap door" death pathway in response to HCMV subversion of apoptosis. HCMV then activates cellular autophagy as a countermeasure to prevent the execution of necroptosis, thereby promoting the continued survival of infected monocytes. Elucidating the mechanisms by which HCMV stimulates monocyte survival is an important step to the development of novel anti-HCMV drugs that prevent the spread of infected monocytes.