Qingchun Zhu, Lixia Yuan, Siying Liu, To Sing Fung, Ding Xiang Liu
Coronavirus hijacks a large number of host factors to complete the replication cycle. However, the engagement of a specific host factor in a particulate viral replication stage and the underlying mechanisms are poorly understood. Our previous transcriptomics studies have found that serum and glucocorticoid-induced kinase 1 (SGK1) is significantly up-regulated in cells infected with coronavirus avian infectious bronchitis virus (IBV). In this study, we confirm that SGK1 is upregulated in cells infected with coronaviruses in three genera, i.e., gammacoronavirus IBV, alphacoronaviruses porcine epidemic diarrhoea virus (PEDV) and betacoronavirus human coronavirus-OC43 (HCoV-OC43). Suppression of SGK1 expression by either siRNA-mediated knockdown or use of an SGK1-specific inhibitor showed the accumulation of significantly more viral structural proteins and higher viral titres in the total cell lysates, but comparatively less in the supernatants, compared with that in the control cells. In cells overexpressing SGK1, the accumulation of viral proteins was significantly reduced in the total lysates, but were slightly upregulated in the culture supernatants. These effects were further reinforced by overexpressing a constitutively active mutant SGK1-S422D and a functionally inactive mutant SGK1-K127M. Furthermore, knockdown and/or inhibition of upstream signalling molecules and downstream effectors demonstrated that IBV infection may activate the PI3K-SGK1-NEDD4L signal axis, playing a regulatory role in the IBV replication cycle. In addition, knockdown of SGK1 was shown to suppress the expression of several proinflammatory cytokines/chemokines and enhance the activation of apoptosis in IBV-infected cells. These findings reveal that induction of SGK1 expression by coronavirus infection may enhance the release of mature virions, identifying a potential target for designing novel intervention approaches.