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

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 a deubiquitinating enzyme that initiates antiviral immunity by deubiquitinating TRAF3 and triggering the antiviral signaling pathway. Here we found that Tim-3-specific knockout in myeloid cells leads to enhanced antiviral immunity in mice with vesicular stomatitis virus (VSV) encephalitis by increasing the type I interferon response. Mechanistically, Tim-3 inhibits the expression of USP25 via STAT1 and interacts with USP25 but does not regulate its posttranslational modification; as a result, Tim-3 inhibits USP25-mediated deubiquitination of TRAF3, promotes K48-linked ubiquitination and degradation of TRAF3, inhibits the phosphorylation of IRF7, and ultimately downregulates the interferon response. These findings provide new insights into the function of Tim-3 in antiviral immunity and its related clinical significance.