SHP-1 interacts with NFκB1 to inhibit its phosphorylation and nuclear translocation to suppress excessive bacterial inflammation

Abstract

The protein tyrosine phosphatase SHP-1 is a key negative regulator in cancer by dephosphorylating multiple target molecules. Specially in the NF{kappa}B signaling, where NF{kappa}B1/Rela dimer translocate to the nucleus and activate target gene transcription, SHP-1 inhibits the phosphorylation of Rela, while its regulation on NF{kappa}B1 has been unknown, especially in pathogen-induced inflammation. Chinese tongue sole, a representative flatfish, has been widely used as a genomics and disease model. Using the teleost and cellular model, we revealed for the first time that SHP-1 inhibits NF{kappa}B1 phosphorylation and nuclear translocation by interacting with NF{kappa}B1, thereby suppressing NF{kappa}B signaling to inhibit bacterial inflammation. In addition, we showed that SHP-1 decreased mortality and alleviated histopathological deterioration, manifested in the inhibition of immune-related pathways and secretion of pro- inflammatory cytokines. Using cellular model, SHP-1 overexpression reduced macrophages M1 polarization, phagocytosis, and oxidative stress, while silencing SHP- 1 exhibited opposite effects. Our findings systematically dissect the functions of SHP- 1 and provide mechanistic insights into the control of inflammation-related diseases. TeaserSHP-1 help maintain the cellular and individual homeostasis by inhibiting the excessive inflammation and immunity via regulating the NF{kappa}B signaling.