SHP-1 suppresses the antiviral innate immune response by targeting TRAF3
SHP-1 suppresses the antiviral innate immune response by targeting TRAF3
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SHP-1 通过靶向 TRAF3 抑制抗病毒先天免疫反应
DOI：
10.1096/fj.202000600rr
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发表时间：
2020-07-23
期刊：
影响因子：
4.8
通讯作者：
Yan, Dapeng
中科院分区：
文献类型：
--
作者：
Hao, Doudou;Wang, Yu;Yan, Dapeng
I型干扰素在对病毒感染的先天免疫应答中起关键作用。据报道，蛋白酪氨酸磷酸酶SHP-1在细菌感染期间通过抑制NF-κ B和MAPK的活化而作为炎性细胞因子产生的负调节剂起作用，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SHP-1的巨噬细胞促进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TRAF 3之间的直接相互作用;这两种蛋白质之间的关联导致CK 1 β向TRAF 3的募集减少，并抑制其K63连接的泛素化; SHP-1通过促进Tyr 116和Tyr 446的去磷酸化来抑制K63连接的TRAF 3泛素化。综上所述，我们的研究结果确定SHP-1作为抗病毒免疫的负调节因子，并表明SHP-1可能是急性病毒感染干预的靶点。
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-kappa B 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 CK1 epsilon 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.