Semaphorin 7A interacts with nuclear factor NF-kappa-B p105 via integrin β1 and mediates inflammation

Semaphorin7a (SEMA7A), a membrane-anchored member of the semaphorin protein family, could be involved in a diverse range of immune responses via its receptor integrin beta 1. Recently, we reported that the SEMA7A(R148W) mutation (a gain-of-function mutation, Sema7a(R145W) in mice) is a risk factor for progressive familial intrahepatic cholestasis and nonalcoholic fatty liver disease via upregulated membrane localization. In this study, we demonstrated that integrin beta 1 is a membrane receptor for nuclear factor NF-kappa-B p105 (NF-kappa B p105) and a critical mediator of inflammation. Integrin beta 1 could interact with the C-terminal domain of NF-kappa B p105 to promote p50 generation and stimulate the NF-kappa B p50/p65 signalling pathway, upregulate TNF-alpha and IL-1 beta levels, and subsequently render hepatocytes more susceptible to inflammation. The induction of integrin beta 1 depends on elevated Sema7a membrane localization. Moreover, we revealed elevated levels of Sema7a(WT) (SEMA7A(WT)) in hepatocellular carcinoma (HCC) patients and an HCC mouse model. In line with our findings, the NF-kappa B p50/p65 pathway could also be activated by high Sema7a expression and repressed by integrin beta 1 silencing. In conclusion, our findings suggest that the Sema7a(R145W) (SEMA7A(R148W)) mutation and high Sema7a(WT) (SEMA7A(WT)) expression both activate the NF-kappa B p50/p65 pathway via integrin beta 1 and play a crucial role in inflammatory responses.