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

Abstract Epstein-Barr virus (EBV) is the first human oncogenic virus identified 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 suggests that the virus may have developed effective viral countermeasures to evade host innate immunity. In this project we performed a functional screen to identify EBV deubiquitinase (DUB) BPLF1 as a potent antagonist of type I interferon production induced by DNA sensors cGAS and STING or RNA sensors RIG-I and MAVS. The large tegument protein BPLF1 exhibited a prominent suppressive effect on cGAS-STING-, and TBK1-induced interferon production. This effect disappeared when Cys61 of BPLF1 was substituted with Ala, which rendered its DUB domain catalytically inactive. This indicated the requirement of DUB activity for BPLF1’s innate immunosuppressive property. BPLF1 was an active DUB for both K63- and K48-linked ubiquitin chains on adaptor protein STING, with no ubiquitin linkage specificity. Our findings suggest that EBV large tegument protein BPLF1 mitigates innate immune responses through its DUB activity on STING and other critical components of innate immune signaling. Supported by HMRF 17160822, RGC C7027-16G and AoE/M-06/08.