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

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-1␤. Yet, the molecular mechanism by which NOD2 can stimulate IL-1␤ 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-1␤ 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-1␤ secretion in a manner that depended on caspase-1 and NOD2. In vitro, Anthrax lethal toxin strongly potentiated IL-1␤ 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-1␤ secretion.inflammasome ͉ lethal toxin ͉ LPS

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

“…In contrast, it appears that in unstimulated macrophages NLRP1 components are not preassembled in a multiprotein complex, but rapidly form protein-protein associations upon stimulation by muramyl dipeptide. 13 In this regard, immunoprecipitation experiments indicate protein-protein interactions are made between NLRP1, ASC, caspase-1, caspase-11, and XIAP in neuronal lysates of sham and spinal cord-injured and brain-injured rodents. 5,6 These studies indicate that the inflammasome components in the CNS are preassembled before activation; however, it is possible that additional inflammasome proteins are recruited into inflammasome complexes as the inflammatory response becomes exacerbated.…”

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

“…25,26 NLRP1 can also associate with NOD2 to mediate caspase-1-dependent IL-1b secretion in response to Bacillus anthracis and MDP. 27,28 Recently a fourth type of inflammasome has been identified, involving the protein absent in melanoma 2 (AIM2) (Figure 1). 29 Despite the lack of NACHT domain, AIM2 can undergo oligodimerization and recruit ASC via PYD in response to double stranded cytosolic DNA through its C-terminal HIN domain.…”

Gut–Liver Axis: Role of Inflammasomes

“…13 Activation of NLRP1 is triggered by (muramyl dipeptide) and the lethal Bacillus anthracis toxin. [14][15][16][17] A unique feature of NLRP1 is that it can localize in the nucleus unlike other inflammasomes which are distributed in the cytoplasm. 18 …”

“…53 Hsu et al showed that the formation of NLRP1 inflammasome was ASC-dependent in humans whereas mouse NLRP1b caused the activation of caspase-1 in an ASC-independent manner. 17 Indeed, muramyl dipeptide can be sensed by NLRP1, like NOD2 and NLRP3. 54 Microbial infection elicits effector mechanisms during the process of host defense.…”