File(s) not publicly available

Suppression of cGAS-STING- and RIG-I-MAVS-mediated innate immune responses by Epstein-Barr virus-encoded tegument protein BPLF1 through de-ubiquitination

posted on 14.09.2020 by Wai Yin Lui
Epstein-Barr virus (“EBV”), a γ-herpesvirus, is the first identified human oncogenic virus. EBV infects more than 90% of the adult population around the world and it is etiologically linked with 2% of human malignancies such as Burkitt’s lymphoma, Hodgkin’s lymphoma, gastric carcinoma and nasopharyngeal carcinoma (“NPC”). The prevalence of EBV infection has suggested that the virus may have developed effective mechanism to evade host innate immunity. In this project, we have screened out a conserved herpesvirus de-ubiquitinase (“DUB”) in EBV, BPLF1, which can potently antagonize the type-I interferon production induced by DNA sensors, cGAS and STING, or RNA sensors, RIG-I and MAVS. Both of the two naturally occurring forms of the large tegument protein BPLF1, the small fragment BPLF1 325 and the full length BPLF1, have also shown potent suppression on cGAS-STING-, RIG-I- and TBK1- induced interferon production. The observed suppressions disappear when the cysteine residue of BPLF1 at position 61 is substituted with alanine, which changed its DUB domain into a catalytically inactive form. This indicates that BPLF1 suppresses innate immunity through its DUB activity. The DUB activity of BPLF1 also promoted EBV infection against cGAS-STING- and TBK1-mediated antiviral responses. The BPLF1 is an effective DUB for all lysine 63 (K63)-, lysine 48 (K48)-and lysine (K27)- linked ubiquitin moieties on adaptor molecule STING and K63- and K48-linked ubiquitin moieties on common adaptor protein TBK1. Physical interaction is found between BPLF1 and STING. The DUB activities of BPLF1 would disturb TBK1-induced IRF3 dimerization. These experiments indicate the DUB activity of the large tegument protein BPLF1 has antagonized innate immune responses through its DUB activities on STING and TBK1 in innate immune signaling.



Logo branding