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.

中文翻译：

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SHP-1 通过靶向 TRAF3 抑制抗病毒先天免疫反应

I 型干扰素在对病毒感染的先天免疫反应中起关键作用。据报道，蛋白酪氨酸磷酸酶 SHP-1 通过抑制细菌感染过程中 NF-κB 和 MAPKs 的激活，作为炎性细胞因子产生的负调节因子，然而，SHP-1 在调节 I 型干扰素中的作用仍然未知。在这里，我们证明敲除或敲低巨噬细胞中的 SHP-1 可促进 HSV-1 和 VSV 诱导的抗病毒免疫反应。相反，L929 细胞中 SHP-1 的过表达抑制了 HSV-1 和 VSV 诱导的免疫反应；抑制直接依赖于磷酸酶活性。我们确定了 SHP-1 和 TRAF3 之间的直接相互作用；这两种蛋白质之间的关联导致 CK1ε 向 TRAF3 的募集减少并抑制其 K63 相关的泛素化；SHP-1 通过促进 Tyr116 和 Tyr446 的去磷酸化来抑制 K63 连接的 TRAF3 泛素化。总之，我们的结果确定 SHP-1 是抗病毒免疫的负调节因子，并表明 SHP-1 可能是干预急性病毒感染的目标。