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<p>The inflammatory response associated with <i>Helicobacter pylori</i> (<i>H. pylori</i>) infection causes a multitude of alterations in the gastric microenvironment, leading to the slow and steady disruption of the gastric epithelial barrier. Activation of NF-κB during <i>H. pylori</i> infection is crucial to this inflammatory response. Here, we show that CYLD, which interacts constitutively with TRAF6, enhances <i>H. pylori’s</i> ADP-heptose-induced activation of the classical NF-κB pathway in gastric epithelial cells. This activating effect of CYLD contrasts with the inhibitory effect of CYLD on receptor-mediated NF-κB activity. Mechanistically, CYLD counteracts the hydrolysis of ubiquitin chains from TRAF6 by deubiquitinylase A20 in a catalytically independent manner, thus supporting the auto-ubiquitinylation of TRAF6 upon activation of NF-κB in early <i>H. pylori</i> infection. In addition, the subsequent classical NF-κB-dependent de novo synthesis of A20 provides a negative feedback loop leading to shutdown not only of the classical but also of the alternative NF-κB pathway. Our findings highlight the regulatory relationship between CYLD and A20 in controlling classical as well as alternative NF-κB signaling in <i>H. pylori</i> infection.</p>

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CYLD-TRAF6 interaction promotes ADP-heptose-induced NF-κB signaling in H. pylori infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月22日

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  • Michelle C C Lim,
  • Gunter Maubach,
  • Michael Naumann

摘要

The inflammatory response associated with Helicobacter pylori (H. pylori) infection causes a multitude of alterations in the gastric microenvironment, leading to the slow and steady disruption of the gastric epithelial barrier. Activation of NF-κB during H. pylori infection is crucial to this inflammatory response. Here, we show that CYLD, which interacts constitutively with TRAF6, enhances H. pylori’s ADP-heptose-induced activation of the classical NF-κB pathway in gastric epithelial cells. This activating effect of CYLD contrasts with the inhibitory effect of CYLD on receptor-mediated NF-κB activity. Mechanistically, CYLD counteracts the hydrolysis of ubiquitin chains from TRAF6 by deubiquitinylase A20 in a catalytically independent manner, thus supporting the auto-ubiquitinylation of TRAF6 upon activation of NF-κB in early H. pylori infection. In addition, the subsequent classical NF-κB-dependent de novo synthesis of A20 provides a negative feedback loop leading to shutdown not only of the classical but also of the alternative NF-κB pathway. Our findings highlight the regulatory relationship between CYLD and A20 in controlling classical as well as alternative NF-κB signaling in H. pylori infection.