A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide.
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.
Departments of Pharmacology and Pathology, University of California at San Diego, La Jolla, CA 92093, USA. lichunghsu@ntu.edu.tw
Li-Chung
LC
Hsu
Syed R
SR
Ali
Shauna
S
McGillivray
Ping-Hui
PH
Tseng
Sanjeev
S
Mariathasan
Eric W
EW
Humke
Lars
L
Eckmann
Jonathan J
JJ
Powell
Victor
V
Nizet
Vishva M
VM
Dixit
Michael
M
Karin
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000276:immunology; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000881:Anthrax / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001408:Bacillus anthracis / Q000276:immunology*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002850:Chromatography, Gel; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D025941:Protein Interaction Mapping; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053583:Interleukin-1beta; C529636:NALP1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; D020170:Caspase 1