Porcine Enteric Coronavirus PEDV Induces the ROS-ATM and Caspase7-CAD-γH2AX Signaling Pathways to Foster Its Replication.
Porcine Enteric Coronavirus PEDV Induces the ROS-ATM and Caspase7-CAD-γH2AX Signaling Pathways to Foster Its Replication.
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猪肠道冠状病毒 PEDV 诱导 ROS-ATM 和 Caspase7-CAD-γH2AX 信号通路促进其复制
DOI：
10.3390/v14081782
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发表时间：
2022-08-15
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影响因子：
--
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中科院分区：
文献类型：
--
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DNA损伤反应（DDR）是真核细胞感受包括病毒感染在内的内外刺激引起的DNA损伤的一种进化上保守的机制。虽然DNA病毒和DDR之间的相互作用已经被广泛研究，但RNA病毒，特别是冠状病毒，如何调节DDR仍然未知。先前的一项研究表明，猪流行性腹泻病毒（PEDV），冠状病毒科α冠状病毒属的成员，在感染的细胞中诱导DDR。然而，其潜在机制尚不清楚。该研究表明，PEDV激活ATM-Chk 2信号传导，而ATM或Chk 2的抑制抑制PEDV感染的早期阶段。此外，我们发现PEDV激活的ATM信号与细胞内ROS的产生相关。有趣的是，我们发现，与典型的γ H2 AX灶不同，PEDV感染导致独特的γ H2 AX染色模式，包括I期（核环染色）、II期（泛核染色）和III期（与凋亡小体共染色），这与凋亡过程高度相似。此外，我们证明PEDV诱导的H2 AX磷酸化依赖于caspase-7和caspase激活的DNA酶（CAD）的激活，而不是ATM-Chk 2。最后，我们表明H2 AX的敲低减弱PEDV复制。综上所述，我们得出结论，PEDV通过ROS-ATM和caspase 7-CAD-γ H2 AX信号通路诱导DDR，以促进其早期复制。
DNA damage response (DDR) is an evolutionarily conserved mechanism by which eukaryotic cells sense DNA lesions caused by intrinsic and extrinsic stimuli, including virus infection. Although interactions between DNA viruses and DDR have been extensively studied, how RNA viruses, especially coronaviruses, regulate DDR remains unknown. A previous study showed that the porcine epidemic diarrhea virus (PEDV), a member of the genus Alphacoronavirus in the Coronaviridae family, induces DDR in infected cells. However, the underlying mechanism was unclear. This study showed that PEDV activates the ATM-Chk2 signaling, while inhibition of ATM or Chk2 dampens the early stage of PEDV infection. Additionally, we found that PEDV-activated ATM signaling correlates with intracellular ROS production. Interestingly, we showed that, unlike the typical γH2AX foci, PEDV infection leads to a unique γH2AX staining pattern, including phase I (nuclear ring staining), II (pan-nuclear staining), and III (co-staining with apoptotic bodies), which highly resembles the apoptosis process. Furthermore, we demonstrated that PEDV-induced H2AX phosphorylation depends on the activation of caspase-7 and caspase-activated DNAse (CAD), but not ATM-Chk2. Finally, we showed that the knockdown of H2AX attenuates PEDV replication. Taken together, we conclude that PEDV induces DDR through the ROS-ATM and caspase7-CAD-γH2AX signaling pathways to foster its early replication.
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