272 Cell SnapShot: Infl ammasomes Maninjay K. Atianand,1 Vijay A. Rathinam,1 and Katherine A. Fitzgerald1 153 1Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA , March 28,2013 ©2013Elsevier Inc. , March DOI http://dx.doi.org/10.1016/j.cell.2013.03.009 Basic inflammasome structure Ca+ Bacterium containing CASR type III secretion system P2X7 receptor Gram-negative Bacteria Salmonella typhimurium Signal 2 ATP Pseuodomonas aeruginosa PLC AC Potassium RECEPTOR NLR or ALR efux Signal 3 Lysosomal destabilization GBP5 PrgJ ADAPTOR ASC Inflammasome Inhibition Bacterial Flagellin complex InsP3 of cAMP mRNA TLR4 Procaspase-1 TRIF + Ca ROS Mitochondrion NLRP3 NAIPs5/6 NAIP2 EFFECTOR Active caspase-1 PKC-δ ROS Type I interferons NLRC4/IPAF pro-IL-1b IL-1b ER stress pro-IL-18 IL-18 Oxidized + mitochondrial DNA Ca P P Signal 1 H+ ASC Active H+ caspase-11 M2 channel NUCLEUS Endoplasmic Trans-golgi Procaspase-1 Procaspase-1 reticulum (ER) Cell death IL-1a & HMGB1 release Active caspase-1 Cell death IL-1a & HMGB1 Cytosolic bacteria pro-IL-1b IL-1b release Francisella tularensis pro-IL-18 IL-18 Listeria monocyotgenes PA Anthrax See online version for legend and references. and legend for version online See lethal toxin Intestinal inflammation Diacylated AIM2 and homeostasis Yersinia pestis lipopeptides ASC LF Microbes ? NLRP6 NLRP12 NLRP7 DNA viruses NLRP1b mCMV Procaspase-1 Vaccinia Herpes viruses (In human monocytes & macrophages) IFI16 ASC KSHV DNA NUCLEUS Procaspase-1 SnapShot: Inflammasomes Maninjay K. Atianand,1 Vijay A. Rathinam,1 and Katherine A. Fitzgerald1 1Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA Large multiprotein complexes referred to as inflammasomes form in the cytosol during infection or in response to endogenous danger signals released from damaged or dying cells and regulate the processing and secretion of IL-1β and IL-18 as well as an inflammatory form of cell death called pyroptosis. Inflammasomes have emerged as central media- tors of the host response to pathogens and are also important contributors to sterile inflammatory diseases. Inflammasome Assembly and Functions The proinflammatory cytokines IL-1β and IL-18 are secreted by many cell types and play crucial roles in both the innate and adaptive arms of host immunity. In contrast to the majority of other proinflammatory cytokines such as TNFα, IL-1β and IL-18 are regulated at both the transcriptional and posttranslational levels. Upon transcriptional induction by PRRs (signal 1), IL-1β and IL-18 are synthesized as biologically inactive proteins, which are subsequently processed by the cysteine protease caspase-1 (ICE). Conversion of procaspase-1 itself into an enzymatically active form, caspase-1, is mediated by the inflammasome (signal 2). There are distinct types of inflammasomes, differentiated by their protein constituents, activators, and effectors. A basic inflammasome complex consists of a cytosolic sensor (which can be either an NLR or a member of the ALR family), the adaptor ASC, and the effector molecule procaspase-1. The inflammasome adaptor ASC has a bipartite structure containing an N-terminal PYD and the C-terminal CARD, and therefore, it acts as a bridge between the sensor (NLRs or ALRs) and the effector procaspase-1 by utilizing homotypic PYD:PYD and CARD:CARD interactions, respectively. In addition to IL-1β and IL-18 processing, active caspase-1 also regulates a form of inflammatory cell death referred to as pyroptosis and leads to unconventional protein secretion. Several inflammasome complexes, which are illustrated here, have been identified in recent years. The NLR-Containing Inflammasomes The NLRP3 inflammasome is the best-studied inflammasome, and its activation is triggered by bacterial, viral, parasitic, and fungal infections as well as by endogenous danger signals such as ATP and uric acid crystals. Although much progress has been made in discovering activators for the NLRP3 inflammasome, what has not been clear is how the assembly of this large multiprotein structure is controlled. Several NLRP3-inflammasome-activating mechanisms have been linked to NLRP3 inflammasome complex assembly and include K+ efflux, lysosomal destabilization, generation of ROS, involvement of Gbp5, presence of cytosolic bacterial RNA during infection, and the release of oxidized mitochondrial DNA. More recently, the murine CASR has also been shown to act upstream of the Nlrp3 inflammasome. The CASR acts via PLC that catalyzes the generation of InsP3, which leads to the release of Ca2+ from the ER leading to the assembly of the Nlrp3 inflammasome. Given the diverse nature of these mechanisms, it is likely that the NLRP3 inflammasome is an indirect sensor of a common cellular event associated with these proposed mechanisms. Recently, a TLR4-TRIF-type I IFN-dependent activation of caspase-11 pathway (signal 3) has been implicated upstream of caspase-1 activation for the NLRP3-inflammasome-mediated IL-1β secretion in response to infection with Gram- negative bacteria, adding yet another layer of complexity to the mechanisms underlying NLRP3-inflammasome-dependent effector functions. The NLRC4 (IPAF) inflammasome is another well-studied inflammasome that assembles via interactions with specific NAIPs in response to the type III secretion apparatus of S. typhimurium. Notably, NLRC4 contains an N-terminal CARD (and lacks the PYD), and therefore, it does not require ASC for inflammasome assembly. The phosphorylation of NLRC4 by protein kinase C-δ is also essential for NLRC4 activation. The NLRP1b and NLRP12 inflammasomes sense anthrax LT and Y. pestis infection, respectively. The NLRP6 inflammasome plays a role in regulating intestinal homeostasis, and the NLRP7 inflammasome has been shown to recognize diacylated lipopeptides in human macrophages. The AIM2 and IFI16 Inflammasome Several groups independently identified AIM2 as a cytosolic receptor for DNA. AIM2 is a member of a larger HIN200- and Pyrin-domain-containing protein family (PYHIN or ALR family). AIM2 binds DNA of self and nonself origin in a sequence-independent manner via its C-terminal HIN200 domain. Notably, the AIM2 inflammasome is the first inflamma- some where a direct receptor:ligand interaction has been formally demonstrated. Subsequent studies in AIM2-deficient mice have further demonstrated an essential role for the AIM2 inflammasome in protective immunity to the intracellular bacterium F. tularensis or following infection with mouse cytomegaovirus. Recently, the related ALR protein, IFI16, has also been linked to inflammasome activation. The IFI16 inflammasome has been implicated in detection of both KSHV and herpes simplex virus infection, where IFI16 is thought to recognize the herpesviral DNA in the nucleus. Abbreviations AIM2, absent in melanoma 2; ALR, AIM2-like receptor; ASC, apoptotic speck-like protein containing CARD; ATP, adenosine triphosphate; CARD, caspase-1 activation and recruitment domain; CASR, calcium-sensing receptor; ER, endoplasmic reticulum; GBP5, guanylate-binding protein 5; HMGB1, high mobility group B1; ICE, IL-1β-converting enzyme; IFI16, interferon inducible protein 16; IL-1, interleukin 1; InsP3, inositol-1,3,5 triphosphate; KSHV, Kaposi-sarcoma-associated herpes virus; LF, lethal factor; LT, lethal toxin; MAMP, microbe-associated molecular pattern; NLR, NOD-like receptors; PA, protective antigen; PLC, phospholipase C; PRR, pattern recognition receptor; PYD, pyrin domain; PYHIN, pyrin and HIN200 domain containing; ROS, reactive oxygen species; TLR, Toll-like receptor; TRIF, Toll/interleukin-1 receptor (TIR)-domain-containing adaptor inducing IFN-β. ACKNOWLEDGMENTS We apologize to the colleagues whose work could not be cited here because of space limitations. 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