Helicobacter pylori CagA activates NF-kappaB by targeting TAK1 for TRAF6-mediated Lys 63 ubiquitination.

Lamb A, Yang XD, Tsang YH, Li JD, Higashi H, Hatakeyama M, Peek RM, Blanke SR, Chen LF
EMBO Rep. 2009 10 (11): 1242-9

PMID: 19820695 · PMCID: PMC2775174 · DOI:10.1038/embor.2009.210

Helicobacter pylori-initiated chronic gastritis is characterized by the cag pathogenicity island-dependent upregulation of proinflammatory cytokines, which is largely mediated by the transcription factor nuclear factor (NF)-kappaB. However, the cag pathogenicity island-encoded proteins and cellular signalling molecules that are involved in H. pylori-induced NF-kappaB activation and inflammatory response remain unclear. Here, we show that H. pylori virulence factor CagA and host protein transforming growth factor-beta-activated kinase 1 (TAK1) are essential for H. pylori-induced activation of NF-kappaB. CagA physically associates with TAK1 and enhances its activity and TAK1-induced NF-kappaB activation through the tumour necrosis factor receptor-associated factor 6-mediated, Lys 63-linked ubiquitination of TAK1. These findings show that polyubiquitination of TAK1 regulates the activation of NF-kappaB, which in turn is used by H. pylori CagA for the H. pylori-induced inflammatory response.

MeSH Terms (14)

Animals Antigens, Bacterial Bacterial Proteins Cell Line Cytokines Gene Expression Regulation Humans Inflammation Lysine MAP Kinase Kinase Kinases Mice NF-kappa B TNF Receptor-Associated Factor 6 Ubiquitin

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