Syntaxin 4 Mediates NF-κB Signaling and Chemokine Ligand Expression via Specific Interaction With IκBβ

Enrichment of human islets with syntaxin 4 (STX4) improves functional beta-cell mass through a nuclear factor-kappa B (NF-kappa B)-dependent mechanism. However, the detailed mechanisms underlying the protective effect of STX4 are unknown. For determination of the signaling events linking STX4 enrichment and downregulation of NF-kappa B activity, STX4 was overexpressed in human islets, EndoC-beta H1 and INS-1 832/13 cells in culture, and the cells were challenged with the proinflammatory cytokines interleukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma individually and in combination. STX4 expression suppressed cytokine-induced proteasomal degradation of I kappa B beta but not I kappa B alpha. Inhibition of IKK beta prevented I kappa B beta degradation, suggesting that IKK beta phosphorylates I kappa B beta. Moreover, the IKK beta inhibitor, as well as a proteosomal degradation inhibitor, prevented the loss of STX4 caused by cytokines. This suggests that STX4 may be phosphorylated by IKK beta in response to cytokines, targeting STX4 for proteosomal degradation. Expression of a stabilized form of STX4 further protected I kappa B beta from proteasomal degradation, and like wild-type STX4, stabilized STX4 coimmunoprecipitated with I kappa B beta and the p50-NF-kappa B. This work proposes a novel pathway wherein STX4 regulates cytokine-induced NF-kappa B signaling in beta-cells via associating with and preventing I kappa B beta degradation, suppressing chemokine expression, and protecting islet beta-cells from cytokine-mediated dysfunction and demise.

Automated summary

Enrichment of human islets with syntaxin 4 improves beta-cell mass through NF-kappa B-dependent mechanism. STX4 suppresses cytokine-induced degradation of I kappa B beta, protecting islet beta-cells from cytokine-mediated dysfunction. This study proposes a novel pathway where STX4 regulates NF-kappa B signaling in beta-cells, preventing I kappa B beta degradation and suppressing chemokine expression.