Department of Immunology, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
National Engineering Research Centre of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University, Chongqing, China.
FASEB J. 2020 Sep;34(9):12392-12405. doi: 10.1096/fj.202000600RR. Epub 2020 Jul 23.
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.
I 型干扰素在病毒感染的固有免疫反应中发挥着关键作用。有报道称，蛋白酪氨酸磷酸酶 SHP-1 在细菌感染过程中通过抑制 NF-κB 和 MAPKs 的激活，作为炎症细胞因子产生的负调节剂发挥作用，然而，SHP-1 在调节 I 型干扰素方面的作用尚不清楚。在这里，我们证明了巨噬细胞中 SHP-1 的敲除或敲低促进了 HSV-1 和 VSV 诱导的抗病毒免疫反应。相反，SHP-1 在 L929 细胞中的过表达抑制了 HSV-1 和 VSV 诱导的免疫反应；抑制作用直接依赖于磷酸酶活性。我们鉴定了 SHP-1 和 TRAF3 之间的直接相互作用；这两种蛋白之间的关联导致 CK1ε 向 TRAF3 的募集减少，并抑制其 K63 连接的泛素化；SHP-1 通过促进 Tyr116 和 Tyr446 的去磷酸化来抑制 TRAF3 的 K63 连接的泛素化。总之，我们的结果确定 SHP-1 是抗病毒免疫的负调节剂，并表明 SHP-1 可能是干预急性病毒感染的靶点。
