CSN-associated c-Cbl control alternative NF-κB/RelB activity in Helicobacter pylori infection.

Authors

Lorena Ferino, Christian Täger, Olga Sokolova, Michael Naumann

Published in

Biochimica et biophysica acta. Molecular cell research. Pages 120234. Oct 05, 2026. Epub Oct 05, 2026.

Abstract

TheThe colonization of the gastric epithelium with Helicobacter pylori elicits a robust nuclear factor kappa-light chain enhancer of activated B cells (NF-κB)-dependent inflammatory response. The bacterial effector molecule adenosine diphosphate-glycero-β-D-manno-heptose (ADP-heptose) triggers both the classical and alternative NF-κB pathways almost simultaneously leading to activation of the transcription factor heterodimers p50/RelA and p52/RelB. Previous studies have demonstrated that the COP9 signalosome complex (CSN) plays an important role in regulating the classical NF-κB pathway through deneddylation of the E3 ligase Skp1-Cullin1-F-Box-β-TRCP (SCF^β-TRCP), while the influence of the CSN on the alternative NF-κB pathway remains unclear. Here, we show that CSN-dependent deneddylation of Cullin-1 controls via the classical NF-κB signaling pathway the upregulation of RelB mRNA and protein expression, enhancing the nuclear translocation of RelB. These findings are supported by the fact that ADP-heptose induces RelB expression in 2D mucosoids derived from 3D organoids from gastric antral glands of the stomach. Blocking neddylation and the activity of SCF^β-TRCP by treatment with the NEDD8-activating enzyme inhibitor MLN4924 prior to H. pylori infection, stabilized IκBα as well as p100 and suppressed RelA and RelB nuclear translocation. Therefore, our data show that CSN-dependent regulation of SCF^β-TRCP controls classical NF-κB signaling and consequently contributes to RelB nuclear translocation and alternative NF-κB activity. For the termination of alternative NF-κB activity, the CSN serves as a hub between constitutively associated c-Cbl and nuclear RelB, allowing c-Cbl-mediated ubiquitinylation of nuclear RelB following H. pylori infection.

PMID:
42833426
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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