The Inflammatory Caspases: Key Players in the Host Response to Pathogenic Invasion and Sepsis This information is current as Amal Nadiri, Melissa K. Wolinski and Maya Saleh of September 29, 2021. J Immunol 2006; 177:4239-4245; ; doi: 10.4049/jimmunol.177.7.4239 http://www.jimmunol.org/content/177/7/4239 Downloaded from References This article cites 91 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/177/7/4239.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY BRIEF REVIEWS The Inflammatory Caspases: Key Players in the Host Response to Pathogenic Invasion and Sepsis Amal Nadiri,1* Melissa K. Wolinski,1† and Maya Saleh2* Caspases are cysteinyl-aspartate-specific proteinases lar partners and may therefore share common mechanisms of known for their role in apoptosis (cell death or apoptotic activation. The CARD domain contains a “death fold” struc- caspases) and proinflammatory cytokine maturation (in- ture also found in the death domain, death effector domain, flammatory caspases). The inflammatory caspases were and pyrin domain (PYD). The caspase catalytic region is com- among the first to be discovered, but only recently have the posed of both large and small subunits with a conserved mechanisms leading to their activation and inhibition be- QACXG active site sequence (where X is R, Q, or G) found in gun to be elucidated. In this review, we examine the bio- the large subunit (Fig. 1B). Caspases recognize a tetrapeptide Downloaded from motif in their substrates and have an absolute specificity for an chemistry, substrates, and function of this unique family aspartic acid residue at the scissile bond. The substrate specific- of inflammatory proteases, highlight the most recent find- ities for caspase-1, -4, -5, and -11 have been determined using ings regarding their regulatory mechanisms, and discuss small peptides in vitro, and were found to be similar with a pref- what remains to be understood about their roles in health erence for the sequence Trp-Glu-His-Asp (WEHD). However, and disease. The Journal of Immunology, 2006, 177: caspase-12 seems to have acquired alterations in its catalytic http://www.jimmunol.org/ 4239–4245. function, as it only recognizes and cleaves itself in rodents (W. Shao and M. Saleh, manuscript in preparation) and appears in- active in humans (6). It is unclear whether the inflammatory aspases12 are essential proteases for the initiation and caspases play a direct role in apoptosis, as we lack mechanistic execution of apoptosis, and for the processing and information about both their execution of cell death and their maturation of the inflammatory cytokines IL-1␤ C cellular “apoptotic” substrates. In this study, we review the and IL-18 (1). In humans, the caspase family includes 13 mem- mechanisms regulating the inflammatory caspases, their func- bers that are classified into three groups according to their phy- tion in inflammation and innate immunity, and what we have by guest on September 29, 2021 logenetic relationship (Fig. 1A), which seems to correlate with recently uncovered about their roles in both sepsis and the host functional relatedness (2). The cell death caspases are initiators immune response to pathogenic invasion. (caspase-2, -8, -9, and -10) and executioners (caspase-3, -6, and -7) of apoptosis. The initiator caspases sense death signals, and Gene orthology and chromosomal localization activate more downstream executioner caspases, which cleave The human inflammatory caspases include caspase-1 (IL-1␤- cellular substrates mediating the changes associated with apo- converting enzyme (ICE)), -4, -5, and -12. Mice have one fewer ptosis. However, this simplistic cascade is not the whole story, inflammatory caspase; caspase-5 is absent, probably having for “apoptotic” caspases, especially caspase-8, appear to have ad- arisen by tandem gene duplication of caspase-4 in higher spe- ditional functions unrelated to cell death. Caspase-8 has been cies. Mouse caspase-11 appears to be the ortholog of human shown to be required for T cell homeostasis, proliferation, and caspase-4. The genes for the inflammatory caspases cluster to- activation (3, 4), and for cell motility under nonapoptotic con- gether on human chromosome 11q22.2-q22.3 and on a syn- ditions (5). It remains to be determined whether other apopto- tenic region on mouse chromosome 9A1. They are arranged tic caspases, besides caspase-8, function in promoting cellular from telomere to centromere as caspase-1, -5, -4, and -12 in hu- survival. mans and as caspase-1, -11, and -12 in mice (Fig. 1C). Two Both inflammatory and apoptotic caspases are synthesized as demonstrated inhibitors of caspase-1, Iceberg and Cop or pseu- inactive zymogens and share a common conserved structure do-ICE, which are CARD-only proteins, are found in close composed of a prodomain and a catalytic region (Fig. 1B). The proximity to caspase-1 in the human but not the murine locus. prodomain contains a caspase-recruitment domain (CARD),3 The arrangement, proximity, as well as the exon-intron struc- which is also present in the cell death initiator caspase-2 and -9, ture of the inflammatory caspases, suggest that they originated suggesting that these caspases might interact with similar cellu- from the same ancestral gene(s). *Department of Medicine, McGill University, Montreal, Canada; and †College of Osteo- 2 Address correspondence and reprint requests to Dr. Maya Saleh, Department of Medi- pathic Medicine, Michigan State University, East Lansing, MI 48824 cine, McGill University, Montreal, Quebec H3A 1A1, Canada. E-mail address: [email protected] Received for publication May 10, 2006. Accepted for publication June 28, 2006. 3 Abbreviations used in this paper: CARD, caspase-recruitment domain; PYD, pyrin do- The costs of publication of this article were defrayed in part by the payment of page charges. main; ICE, IL-1␤-converting enzyme; LRR, leucine-rich repeat; NLR, NOD-LRR; NAIP, This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. neuronal apoptosis inhibitor protein; NALP, Nacht, CRR, and PyD-containing protein; Section 1734 solely to indicate this fact. IPAF, ice protease activating factor; RIP, receptor-interacting protein; ER, endoplasmic 1 A.N. and M.K.W. contributed equally to this review. reticulum; Crm, cytokine response modifier; SNP, single nucleotide polymorphism. Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 4240 BRIEF REVIEWS: THE INFLAMMATORY CASPASES FIGURE 2. Transcriptional splice variants of the human and mice inflam- Downloaded from matory caspases. Black boxes represent exons. Black lines represent introns. Dark red represents untranslated regions. The red asterisk denotes the position of the human caspase-12 SNP in exon 4. Like caspase-1, mouse caspase-11 is expressed in the hemo- poietic and the CNS but found at low levels in most tissues. It is highly induced by LPS and IFN-␥ (18–21). In addition, it is http://www.jimmunol.org/ induced in the duodenum and jejunum following intestinal FIGURE 1. Phylogenetic relationship, domain organization, and chromo- somal localization of the inflammatory caspases. A, Phylogenetic tree of the hu- mucositis, and in the brain following hypoxic and ischemic man caspase family. The inflammatory caspases are shown in red and the apo- brain injury (11, 22). ptosis caspases in black. B, The inflammatory caspases consist of a CARD or Caspase-12 is expressed in almost all tissues at the RNA level CARD-containing prodomain, and a large and a small catalytic subunit. For with the highest expression observed in the lung, stomach, and comparison, the CARD-only proteins COP, ICEBERG, and the caspase-12 small intestine (23, 24). Its constitutive protein expression, short variant are shown in gray. C, The human and mice inflammatory caspase however, is restricted to skeletal muscle, heart, brain, liver, loci on human chromosome 11q22 and mouse chromosome 9A1, respectively. eye, and testis. Its expression is low in the lymph nodes, thy- by guest on September 29, 2021 The genes are arranged from centromere to telomere with caspase-12 being ␥ closer to the telomere. mus, and spleen (25), but is highly inducible by IFN- and bacterial components in various cells including splenocytes and macrophages (24). Expression patterns and gene regulation The inflammatory caspases are held in check at different levels. Substrates Alternative splicing, tissue-specific distribution and gene induc- Very little is known about the physiologic substrates of the in- tion by inflammatory mediators add to the complexity of their flammatory caspases. Caspase-1 is known to cleave pro-IL-1␤ regulation. In total, there are 18 transcripts encoded by the hu- (26), pro-IL-18 (27), the related IL-1 family member IL-1F7b, man inflammatory caspases and 3 by their murine orthologs also known as IL-1H4 (28), and more recently IL-33 (29). It (Fig. 2). Alternative splicing of human caspase-1 yields five dif- has also been shown in vitro to process actin (30), the kinase ferent transcripts and that of human caspase-4 and -12 results in PITSLRE (31), and parkin (32).