Multi-protomics analysis identified host cellular pathways perturbed by tick-borne encephalitis virus infection

• Published in: Nature communications 2024-11, Vol.15 (1), p.10435-17, Article 10435
• Main Authors: Sui, Liyan, Wang, Wenfang, Guo, Xuerui, Zhao, Yinghua, Tian, Tian, Zhang, Jinlong, Wang, Heming, Xu, Yueshan, Chi, Hongmiao, Xie, Hanxi, Xu, Wenbo, Liu, Nan, Zhao, Li, Song, Guangqi, Wang, Zedong, Zhang, Kaiyu, Che, Lihe, Zhao, Yicheng, Wang, Guoqing, Liu, Quan
• Format: Article
• Language: English
• Subjects: 101/58; 13/95; 38/47; 38/79; 631/326/596/2097; 631/326/596/2555; 64/60; 692/699/255/2514; AKT1 protein; Animals; Antiviral activity; Antiviral agents; Antiviral Agents - pharmacology; Arachnids; Autophagy; Cellular structure; Damage; Deacetylation; Deoxyribonucleic acid; Disease transmission; DNA; DNA Damage; DNA repair; Drugs; Encephalitis; Encephalitis Viruses, Tick-Borne - genetics; Encephalitis Viruses, Tick-Borne - pathogenicity; Encephalitis Viruses, Tick-Borne - physiology; Encephalitis, Tick-Borne - metabolism; Encephalitis, Tick-Borne - virology; Evolution; Flaviviridae; Hemorrhagic fever; Host-Pathogen Interactions; Humanities and Social Sciences; Humans; Immune response; Immunity, Innate; Immunosuppressive agents; Infections; Innate immunity; Kinases; multidisciplinary; Pathogenesis; Phosphoproteins - genetics; Phosphoproteins - metabolism; Proteins; Proteome - metabolism; Proteomes; Proteomics; Proteomics - methods; Proto-Oncogene Proteins c-akt - metabolism; Science; Science (multidisciplinary); SIRT1 protein; Tick-borne encephalitis; Vaccines; Viral infections; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54628-w

Tick-borne encephalitis virus (TBEV) represents a pivotal tick-transmitted flavivirus responsible for severe neurological consequences in Europe and Asia. The emergence of TBEV genetic mutations and vaccine-breakthrough infections, along with the absence of effective vaccines and specific drugs for other tick-borne flaviviruses associated with severe encephalitis or hemorrhagic fever, underscores the urgent need for progress in understanding the pathogenesis and intervention strategies for TBEV and related flaviviruses. Here we elucidate cellular alterations in the proteome, phosphoproteome, and acetylproteome upon TBEV infection. Our findings reveal a substantial impact of TBEV infection on the innate immune response, ribosomal biogenesis, autophagy, and DNA damage response (DDR). Mechanically, the non-structural protein NS5 of TBEV impedes DNA damage repair by interacting with SIRT1 to suppress the deacetylation of KAP1 and Ku70. Additionally, the precursor membrane protein prM induces autophagy via associating with AKT1 while constrains autolysosome formation through binding to VPS11. Inhibitors targeting DDR, as well as specific kinases, exhibit potent antiviral activity, suggesting the dysregulated pathways and kinases as potential targets for antiviral intervention. These results from our study contribute to elucidating the pathogenesis and offers insights for developing effective antiviral drugs against TBEV and other tick-borne flaviviruses. Here, Sui et al. use multi-proteomics to analyse tick-borne encephalitis virus-infected cells and identify host cellular pathways perturbed by viral infection.