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Cell Death Differ. 2017 Sep;24(9):1621-1631. doi: 10.1038/cdd.2017.89. Epub 2017 Jun 2.

Pathogen-induced ubiquitin-editing enzyme A20 bifunctionally shuts off NF-κB and caspase-8-dependent apoptotic cell death.

Author information

1
Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg 39120, Germany.
2
Research group Translational Inflammation Research, Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg 39106, Germany.
3
Division of Microbiology, Department of Biology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen 91058, Germany.
4
Institute of Medical Microbiology and Hospital Hygiene, Otto von Guericke University, Magdeburg 39120, Germany.
5
Organ-specific Immune Regulation, Helmholtz-Center for Infection Research, Braunschweig 38124, Germany.

Abstract

The human pathogen Helicobacter pylori infects more than half of the world's population and is a paradigm for persistent yet asymptomatic infection but increases the risk for chronic gastritis and gastric adenocarcinoma. For successful colonization, H. pylori needs to subvert the host cell death response, which serves to confine pathogen infection by killing infected cells and preventing malignant transformation. Infection of gastric epithelial cells by H. pylori provokes direct and fast activation of the proinflammatory and survival factor NF-κB, which regulates target genes, such as CXCL8, BIRC3 and TNFAIP3. However, it is not known how H. pylori exploits NF-κB activation and suppresses the inflammatory response and host apoptotic cell death, in order to avert the innate immune response and avoid cell loss, and thereby enhance colonization to establish long-term infection. Here we assign for the first time that H. pylori and also Campylobacter jejuni-induced ubiquitin-editing enzyme A20 bifunctionally terminates NF-κB activity and negatively regulates apoptotic cell death. Mechanistically, we show that the deubiquitinylase activity of A20 counteracts cullin3-mediated K63-linked ubiquitinylation of procaspase-8, therefore restricting the activity of caspase-8. Interestingly, another inducible NF-κB target gene, the scaffold protein p62, ameliorates the interaction of A20 with procaspase-8. In conclusion, pathogen-induced de novo synthesis of A20 regulates the shut-off of the survival factor NF-κB but, on the other hand, also impedes caspase-8-dependent apoptotic cell death so as to promote the persistence of pathogens.

PMID:
28574503
PMCID:
PMC5563994
DOI:
10.1038/cdd.2017.89
[Indexed for MEDLINE]
Free PMC Article

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