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Src homology region 2 domain-containing phosphatase 1 (SHP1), encoded by the  protein tyrosine phosphatase nonreceptor type 6  ( ptpn6 ) gene, belongs to the family of protein tyrosine phosphatases (PTPs) and participates in multiple signaling pathways of immune cells. However, the mechanism of SHP1 in regulating fish immunity is largely unknown. In this study, we first identified two gibel carp ( Carassius gibelio )  ptpn6  homeologs ( Cgptpn6-A  and  Cgptpn6-B ), each of which had three alleles with high identities. Then, relative to  Cgptpn6-B , dominant expression in adult tissues and higher upregulated expression of  Cgptpn6-A  induced by polyinosinic-polycytidylic acid (poly I:C), poly deoxyadenylic-deoxythymidylic (dA:dT) acid and spring viremia of carp virus (SVCV) were uncovered. Finally, we demonstrated that  Cg SHP1-A (encoded by the  Cgptpn6-A  gene) and  Cg SHP1-B (encoded by the  Cgptpn6-B  gene) act as negative regulators of the RIG-I-like receptor (RLR)-mediated interferon (IFN) response  via  two mechanisms: the inhibition of  Ca TBK1-induced phosphorylation of  Ca MITA shared by  Cg SHP1-A and  Cg SHP1-B, and the autophagic degradation of  Ca MITA exclusively by  Cg SHP1-A. Meanwhile, the data support that  Cg SHP1-A and  Cg SHP1-B have sub-functionalized and that  Cg SHP1-A overwhelmingly dominates  Cg SHP1-B in the process of RLR-mediated IFN response. The current study not only sheds light on the regulative mechanism of SHP1 in fish immunity, but also provides a typical case of duplicated gene evolutionary fates.

Two Duplicated Ptpn6 Homeologs Cooperatively and Negatively Regulate RLR-Mediated IFN Response in Hexaploid Gibel Carp