Tim-3 promotes viral infection by suppressing USP25-TRAF3-IRF7 signaling pathway

Abstract

Tim-3, an immune checkpoint inhibitor, plays key roles in maintaining immune homeostasis and is involved in viral evasion. However, the precise role of Tim-3 in viral infection remains to be determined. USP25 is one of the deubiquitinating enzymes that serves to initiate antiviral immunity by deubiquitinating TRAF3 and triggering the anti-viral signaling pathway. Here we found that Tim-3 specific knockout in myeloid cells leads to enhanced anti-viral immunity in mice with VSV encephalitis by increasing type I interferon response. Mechanistically, Tim-3 inhibits the expression of USP25 via STAT1, interacts with USP25 but does not regulate its post-translational modification, and as a result, Tim-3 inhibits USP25 mediated deubiquitination of TRAF3, promotes k48-linked ubiquitination and degradation of TRAF3, and then inhibits the phosphorylation of IRF7, finally down-regulates the interferon response. These findings provide new insights into the function of Tim-3 in antiviral immunity and its related clinical significance.