SHP‐1 suppresses the antiviral innate immune response by targeting TRAF3

Hao, Doudou; Wang, Yu; Li, Liuyan; Qian, Gui; Liu, Jing; Li, Manman; Zhang, Yihua; Zhou, Ruixue; Yan, Dapeng

Type I interferons play a pivotal role in innate immune response to virus infection. The protein tyrosine phosphatase SHP‐1 was reported to function as a negative regulator of inflammatory cytokine production by inhibiting activation of NF‐κB and MAPKs during bacterial infection, however, the role of SHP‐1 in regulating type I interferons remains unknown. Here, we demonstrated that knockout or knockdown of SHP‐1 in macrophages promoted both HSV‐1‐ and VSV‐induced antiviral immune response. Conversely, overexpression of SHP‐1 in L929 cells suppressed the HSV‐1‐ and VSV‐induced immune response; suppression was directly dependent on phosphatase activity. We identified a direct interaction between SHP‐1 and TRAF3; the association between these two proteins resulted in diminished recruitment of CK1ε to TRAF3 and inhibited its K63‐linked ubiquitination; SHP‐1 inhibited K63‐linked ubiquitination of TRAF3 by promoting dephosphorylation at Tyr116 and Tyr446. Taken together, our results identify SHP‐1 as a negative regulator of antiviral immunity and suggest that SHP‐1 may be a target for intervention in acute virus infection.