A Gammacoronavirus, Avian Infectious Bronchitis Virus, and an Alphacoronavirus, Porcine Epidemic Diarrhea Virus, Exploit a Cell Survival Strategy by Upregulating cFOS To Promote Virus Replication

• Published in: Journal of virology 2021-01, Vol.95 (4)
• Main Authors: Yuan, Li Xia, Liang, Jia Qi, Zhu, Qing Chun, Dai, Guo, Li, Shumin, Fung, To Sing, Liu, Ding Xiang
• Format: Article
• Language: English
• Subjects: Virus-Cell Interactions
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.02107-20

Coronaviruses have evolved a variety of strategies to optimize the cellular microenvironment for efficient replication. In this study, we report the induction of AP-1 transcription factors by coronavirus infection based on genome-wide analyses of differentially expressed genes in cells infected with the avian coronavirus infectious bronchitis virus (IBV). Most members of the AP-1 transcription factors were subsequently found to be upregulated during the course of IBV and porcine epidemic diarrhea virus (PEDV) infection of cultured cells as well as in IBV-infected chicken embryos. Further characterization of the induction kinetics and functional roles of cFOS in IBV replication demonstrated that the upregulation of cFOS at early to intermediate phases of IBV replication cycles suppresses IBV-induced apoptosis and promotes viral replication. Blockage of the nuclear translocation of cFOS by the peptide inhibitor nuclear localization signal peptide (NLSP) suppressed IBV replication and apoptosis, ruling out the involvement of the cytoplasmic functions of cFOS in the replication of IBV. Furthermore, knockdown of extracellular signal-regulated kinase 1/2 (ERK1/2) and inhibition of Jun N-terminal protein kinase (JNK) and p38 kinase activities reduced cFOS upregulation and IBV replication. This study reveals an important function of cFOS in the regulation of coronavirus-induced apoptosis, facilitating viral replication. IMPORTANCE The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by a newly emerged zoonotic coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]), highlights the importance of coronaviruses as human and animal pathogens and our knowledge gaps in understanding the cellular mechanisms, especially the mechanisms shared among human and animal coronaviruses, exploited by coronaviruses for optimal replication and enhanced pathogenicity. This study reveals that the upregulation of cFOS, along with other AP-1 transcription factors, as a cell survival strategy is such a mechanism utilized by coronaviruses during their replication cycles. Through the induction and regulation of apoptosis of infected cells at early to intermediate phases of the replication cycles, subtle but appreciable differences in coronavirus replication efficiency were observed when the expression levels of cFOS were manipulated in the infected cells. As the AP-1 transcription factors are multifunctional, further studies of their regulatory roles in pr