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

Abstract

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 β1. 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 β1 is a membrane receptor for nuclear factor NF-kappa-B p105 (NF-κB p105) and a critical mediator of inflammation. Integrin β1 could interact with the C-terminal domain of NF-κB p105 to promote p50 generation and stimulate the NF-κB p50/p65 signalling pathway, upregulate TNF-α and IL-1β levels, and subsequently render hepatocytes more susceptible to inflammation. The induction of integrin β1 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-κB p50/p65 pathway could also be activated by high Sema7a expression and repressed by integrin β1 silencing. In conclusion, our findings suggest that the Sema7a^R145W (SEMA7A^R148W) mutation and high Sema7a^WT (SEMA7A^WT) expression both activate the NF-κB p50/p65 pathway via integrin β1 and play a crucial role in inflammatory responses.

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