UMP‐CMP kinase 2 inhibits ZIKV replication through activation of type I IFN signaling pathway

Abstract

Cytidine/uridine monophosphate kinase 2 (UMP‐CMP kinase 2, CMPK2) has been reported as an antiviral interferon‐stimulated gene (ISG). We previously observed that the expression of CMPK2 was significantly upregulated after Zika Virus (ZIKV) infection in A549 cells. However, the association and the underlying mechanisms between CMPK2 induction and ZIKV replication remain to be determined. We investigated the induction of CMPK2 during ZIKV infection and the effect of CMPK2 on ZIKV replication in A549, U251, Vero, IFNAR‐deficient U5A and its parental 2fTGH cells, Huh7 and its RIG‐I‐deficient derivatives Huh7.5.1 cells. The activation status of Jak‐STAT signaling pathway was determined by detecting the phosphorylation level of STAT1, the activity of interferon stimulated response element (ISRE) and the expression of several interferon stimulated genes (ISGs). We found that ZIKV infection induced CMPK2 expression through an IFNAR and RIG‐I dependent manner. Overexpression of CMPK2 inhibited while CMPK2 knockdown promoted ZIKV replication in A549 and U251 cells. Mechanically, we found that CMPK2 overexpression increased IFNβ expression and activated Jak/STAT signaling pathway as shown by the increased level of p‐STAT1, enhanced activity of ISRE, and the upregulated expression of downstream ISGs. These findings suggest that ZIKV infection induced CMPK2 expression, which inhibited ZIKV replication and serves as a positive feedback regulator for IFN‐Jak/STAT pathway.

Zika virus infection in a cell culture model reflects the transcriptomic signatures in patients

“…Cytidine/uridine monophosphate kinase 2 (CMPK2) is also a type I interferon stimulated gene that was previously shown to affect translation and restrict ZIKV infection [91][92][93]. Indeed, we also found in ZIKV infected A549 cells that CMPK2 was upregulated compared to mock infected cells (Figure S3).…”

“…Interestingly, HERC5-directed ISG15 modification of ALIX and CHIMP4A, two proteins associated with the ESCRT pathway, resulted in the turnover of the two ESCRT proteins and increased tick-borne encephalitis flavivirus infection [90]. Cytidine/uridine monophosphate kinase 2 (CMPK2) is also a type I interferon stimulated gene that was previously shown to affect translation and restrict ZIKV infection [91–93]. Indeed, we also found in ZIKV infected A549 cells that CMPK2 was upregulated compared to mock infected cells ( Figure S3 ).…”