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

Li, G.; Du, L.; Chen, J.; Du, C.; Wang, C.; Bao, B.; LV, Z.; Xing, C.; Liang, M.; Wang, L.; Xie, S.; Li, Y.; Wang, Z.; Zhang, J.; Han, G.

doi:10.1101/2024.08.19.608574

bioRxiv · 10.1101/2024.08.19.608574

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

Li, G.·Du, L.·Chen, J.·Du, C.·Wang, C.·Bao, B.·LV, Z.·Xing, C.·Liang, M.·Wang, L.·Xie, S.·Li, Y.·Wang, Z.·Zhang, J.·Han, G.

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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.

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Li, G., Du, L., Chen, J., Du, C., Wang, C., Bao, B., LV, Z., Xing, C., Liang, M., Wang, L., Xie, S., Li, Y., Wang, Z., Zhang, J., Han, G.. 2024-08-19. Tim-3 promotes viral infection by suppressing USP25-TRAF3-IRF7 signaling pathway. https://doi.org/10.1101/2024.08.19.608574

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