Kinases Associated with Herpes Zoster Virus Infection Unveiled by Phosphoromics Profiling

Juan Xia,1 Hongxiang Xu,2 Xinpei Wang,2 Yang Mei,3 Tianyu Zhang,2 Yiping Dong,4 Wei Li,5 Zhong-Liang Deng6 1Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China; 2Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environment of Three Gorges Reservoir, Ministry of Education, School of Life Sciences, Southwest University, Chongqing, 400715, People’s Republic of China; 3Department of Pain, The Thirteenth People’s Hospital of Chongqing (Chongqing Geriatrics Hospital), Chongqing, 400053, People’s Republic of China; 4Department of Bioengineering and Medical Imaging, Army Medical University (Third Military Medical University), Chongqing, 400038, People’s Republic of China; 5Department of Pain, Chongqing Traditional Chinese Medicine Hospital,400021 Chongqing, China The Thirteenth People’s Hospital of Chongqing (Chongqing Geriatrics Hospital), Chongqing, People’s Republic of China; 6Department of Orthopedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of ChinaCorrespondence: Zhong-Liang Deng, Email [email protected] Wei Li, Email [email protected]: Reactivation of varicella-zoster virus (VZV) causes herpes zoster (HZ) in humans and elicits a VZV-specific immune response. However, the effect of VZV on host protein post-translational modifications (PTMs) remains largely unknown.Objective: In this study, we investigated global changes in phosphorylation levels in HZ patients with postherpetic neuralgia (PHN) compared to healthy controls.Methods: Using publicly available datasets, we found that the serine/threonine protein kinase and phosphatase pathways are significantly regulated by VZV infection, suggesting that VZV infection might globally alter the phosphorome of the host. To test this hypothesis, the phosphoproteomes of peripheral blood collected from HZ patients with PHN were profiled and differentially phosphorylated proteins were identified.Results: The enhanced phosphorylated proteins were involved in pathways including complement activation, coagulation cascades, and endoplasmic reticulum protein processing. Variations in the phosphorylation levels of several proteins were highly consistent with a previously published proteomic study, indicating the synergistic regulation of protein translation and post-translational modification.Conclusion: Notably, kinase-substrate enrichment analysis identified CSNK2A1 and PRKACA as potential response kinases, whereas their transcription and protein levels were experimentally validated to be significantly altered after VZV infection, showing the same trend. Furthermore, Mendelian randomization (MR) analysis revealed that decreased expression of CSNK2A1 may lead to a higher risk of HZ, indicating a vital role of this kinase during anti-VZV infection. Collectively, our findings provide valuable insights into the molecular mechanisms underlying VZV infection and highlight potential therapeutic targets for further investigation.Keywords: Varicella-zoster virus, phosphoproteome, kinase, CSNK2A1, PRKACA