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

posted on 01.02.2021, 16:21 by Ada Admin, Rajakrishnan Veluthakal, Eunjin Oh, Miwon Ahn, Diti Chatterjee-Bhowmick, Debbie C. Thurmond
Enrichment of human islets with Syntaxin 4 (STX4) improves functional β-cell mass through a nuclear factor- kB (NF-kB)-dependent mechanism. However, the detailed mechanisms underlying the protective effect of STX4 are unknown. To determine the signaling events linking STX4 enrichment and downregulation of NF-kB activity, STX4 was overexpressed in human islets, EndoC-βH1 and INS-1 832/13 cells in culture, and the cells were challenged with the proinflammatory cytokines interleukin-1β, tumor necrosis factor-a and interferon-g, individually and in combination. STX4 expression suppressed cytokine-induced proteasomal degradation of IkBβ but not IkBa. Inhibition of IKKβ prevented IkBβ degradation, suggesting that IKKβ phosphorylates IkBβ. Moreover, the IKKβ inhibitor, as well as a proteosomal degradation inhibitor, prevented the loss of STX4 caused by cytokines. This suggests that STX4 may be phosphorylated by IKKβ in response to cytokines, targeting STX4 for proteosomal degradation. Expression of a stabilized form of STX4 further protected IkBβ from proteasomal degradation, and like wildtype STX4, stabilized STX4 coimmunoprecipitated with IkBβ and the NF-kB p50 subunit. This work proposes a novel pathway wherein STX4 regulates cytokine-induced NF-kB signaling in β-cells via associating with and preventing IkBβ degradation, suppressing chemokine expression, and protecting islet β-cells from cytokine-mediated dysfunction and demise.


This study was supported by grants from the National Institutes of Health (DK067912, DK112917 and DK102233 to D.C.T.), the Juvenile Diabetes Research Foundation (17-2013-454 to D.C.T.), and the Wanek Project to Cure Type 1 Diabetes at the City of Hope.