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PMID: 18511561 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 105 ·No. 22 ·2008-06-03 ·Pages 7803-8

Hsu LC, Ali SR, McGillivray S, Tseng PH, Mariathasan S, Humke EW, Eckmann L, Powell JJ, Nizet V, Dixit VM, Karin M

Abstract

NOD2, a NOD-like receptor (NLR), is an intracellular sensor of bacterial muramyl dipeptide (MDP) that was suggested to promote secretion of the proinflammatory cytokine IL-1beta. Yet, the molecular mechanism by which NOD2 can stimulate IL-1beta secretion, and its biological significance were heretofore unknown. We found that NOD2 through its N-terminal caspase recruitment domain directly binds and activates caspase-1 to trigger IL-1beta processing and secretion in MDP-stimulated macrophages, whereas the C-terminal leucine-rich repeats of NOD2 prevent caspase-1 activation in nonstimulated cells. MDP challenge induces the association of NOD2 with another NLR protein, NALP1, and gel filtration analysis revealed the formation of a complex consisting of NOD2, NALP1, and caspase-1. Importantly, Bacillus anthracis infection induces IL-1beta secretion in a manner that depended on caspase-1 and NOD2. In vitro, Anthrax lethal toxin strongly potentiated IL-1beta secretion, and that response was NOD2 and caspase-1-dependent. Thus, NOD2 plays a key role in the B. anthracis-induced inflammatory response by being a critical mediator of IL-1beta secretion.

MeSH Terms
Acetylmuramyl-Alanyl-Isoglutamine/immunology Adaptor Proteins, Signal Transducing/metabolism Animals Anthrax/immunology Apoptosis Regulatory Proteins/metabolism Bacillus anthracis/immunology Caspase 1/genetics,metabolism Cell Line Chromatography, Gel Humans Inflammation/immunology,microbiology Interleukin-1beta/metabolism Macrophages/immunology Mice Mice, Inbred Strains Mutation Nod2 Signaling Adaptor Protein/genetics,metabolism Protein Interaction Mapping Receptor-Interacting Protein Serine-Threonine Kinase 2 Receptor-Interacting Protein Serine-Threonine Kinases/genetics,metabolism
Chemicals
Adaptor Proteins, Signal Transducing Apoptosis Regulatory Proteins Interleukin-1beta NALP1 protein, mouse Nod2 Signaling Adaptor Protein Nod2 protein, mouse Acetylmuramyl-Alanyl-Isoglutamine Receptor-Interacting Protein Serine-Threonine Kinase 2 Receptor-Interacting Protein Serine-Threonine Kinases Ripk2 protein, mouse Caspase 1
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Hsu Li-Chung
Departments of Pharmacology and Pathology, University of California at San Diego, La Jolla, CA 92093, USA. [email protected]
Ali Syed R
McGillivray Shauna
Tseng Ping-Hui
Mariathasan Sanjeev
Humke Eric W
Eckmann Lars
Powell Jonathan J
Nizet Victor
Dixit Vishva M
Karin Michael
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0802726105
Email
[email protected]
Published
2008-06-03
Epub
2008-00-29
Pages
7803-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2409384
Subset
IM
Grants
NIAID NIH HHS · R21 AI053528-02 · United States
NIAID NIH HHS · R21 AI053528 · United States
NIAID NIH HHS · R01 AI061712-05 · United States
NIAID NIH HHS · R01 AI061712 · United States
Medical Research Council · MC_U105960399 · United Kingdom
NIEHS NIH HHS · R01 ES006376 · United States
External Links
PubMed source DOI: 10.1073/pnas.0802726105 PMC Full Text View journal details
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