Inflammasomes: guardians of cytosolic sanctity.
The innate immune system is critical in recognizing bacterial and viral infections to evoke a proper immune response. Certain members of the intracellular nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family detect microbial components in the cytosol and trigger the assembly of large caspase-1-activating complexes termed inflammasomes. Autoproteolytic maturation of caspase-1 zymogens within these inflammasomes leads to maturation and secretion of the pro-inflammatory cytokines interleukin-1 beta (IL-1 beta) and IL-18. The NLR proteins ICE protease-activating factor (IPAF), NALP1b (NACHT domain-, leucine-rich repeat-, and PYD-containing protein 1b), and cryopyrin/NALP3 assemble caspase-1-activating inflammasomes in a stimulus-dependent manner. Bacterial flagellin is sensed by IPAF, whereas mouse NALP1b detects anthrax lethal toxin. Cryopyrin/NALP3 mediates caspase-1 activation in response to a wide variety of microbial components and in response to crystalline substances such as the endogenous danger signal uric acid. Genetic variations in Nalp1 and cryopyrin/Nalp3 are associated with autoinflammatory disorders and increased susceptibility to microbial infection. Further understanding of inflammasomes and their role in innate immunity should provide new insights into the mechanisms of host defense and the pathogenesis of autoimmune diseases.
Lamkanfi
Mohamed
M
Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA.
Dixit
Vishva M
VM
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D053468:CARD Signaling Adaptor Proteins / Q000276:immunology / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007239:Infections / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D007249:Inflammation; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D046912:Multiprotein Complexes / Q000276:immunology / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D020382:Interleukin-18; D053583:Interleukin-1beta; D046912:Multiprotein Complexes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; C435692:NLRC4 protein, human; C427903:NLRP1 protein, human; C453881:NLRP3 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D020170:Caspase 1