Kinases Responding to Herpes Zoster Virus Infection Unveiled by Phosphoromics Profiling

Reactivation of varicella-zoster virus (VZV) causes herpes zoster (HZ) in humanity and elicits VZV-specific immune response. Yet the impact of VZV on host proteins post-translational modifications (PTMs) remains largely untapped. In this study, we investigated the global changes of phosphorylation levels in HZ patients compared with healthy control. Through publicly available datasets, we found that the serine/threonine protein kinase and phosphatase pathways were significantly regulated by VZV infection, suggesting that VZV infection might globally alter the phosphorome of host. To test this hypothesis, the phosphoproteomes of peripheral blood collected from HZ patients were profiled, differentially phosphorylated proteins after VZV infection were identified. The enhanced phosphorylated proteins were involved in pathways including complement activation, coagulation cascades, and endoplasmic reticulum protein processing. Variations in phosphorylation level of several proteins are highly corresponding to a previous published proteomic study, indicating synergistic regulation of the protein translation and post-translational modification. Notably, kinase-substrate enrichment analysis identified CSNK2A1 and PRKACA as potential response kinase, while their transcription and protein levels were experimentally validated to be significantly altered after VZV infection and showed the same trend. Furthermore, Mendelian randomization (MR) analysis revealed decreased expression of CSNK2A1 may lead to higher risk of HZ, manifesting vital role of this kinase during anti-VZV infection. Together, our findings provide valuable insights into the molecular mechanisms underlying VZV infection and highlight potential therapeutic targets for further investigation.