Helicobacter pylori CagA activates NF-kappaB by targeting TAK1 for TRAF6-mediated Lys 63 ubiquitination.
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.
Lamb
Acacia
A
Department of Biochemistry, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Yang
Xiao-Dong
XD
Tsang
Ying-Hung N
YH
Li
Jiang-Dong
JD
Higashi
Hideaki
H
Hatakeyama
Masanori
M
Peek
Richard M
RM
Blanke
Steven R
SR
Chen
Lin-Feng
LF
D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D008239:Lysine / Q000737:chemistry*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D008239:Lysine; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D025801:Ubiquitin; D000099151:MAP Kinase Kinase Kinase 7; C080866:cagA protein, Helicobacter pylori