A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide
Journal
Proceedings of the National Academy of Sciences of the United States of America
Journal Volume
105
Journal Issue
22
Pages
7803-7808
Date Issued
2008-06-03
Author(s)
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
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.
Subjects
Inflammasome | Lethal toxin | LPS
Publisher
National Academy of Sciences
Type
journal article