37
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Pyrin- and CARD-only Proteins as Regulators of NLR Functions

      review-article
      1 , 2 , 1 , *
      Frontiers in Immunology
      Frontiers Media S.A.
      pyrin, CARD, NLR, inflammasome, NF-kappaB, inhibitors

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Upon activation Nod-like receptors (NLRs) assemble into multi-protein complexes such as the NODosome and inflammasome. This process relies upon homo domain interactions between the structurally related Pyrin and caspase-recruitment (CARD) domains and adaptor proteins, such as ASC, or effector proteins, such as caspase-1. Although a variety of NLRP and NLRC complexes have been described along with their activating stimuli and associated proteins, less familiar are processes limiting assembly and/or promoting dissociation of NLR complexes. Given the importance of limiting harmful, chronic inflammation, such regulatory mechanisms are significant and likely numerous. Proteins comprised of a solitary Pyrin domain (Pyrin-only) or CARD domain (CARD-only) posses an obvious potential ability to act as competitive inhibitors of NLR complexes. Indeed, both Pyrin-only proteins (POPs) and CARD-only proteins (COPs) have been described as regulators of caspase-1 and/or NLR-inflammasome activation and not surprisingly as factors mediating pathogenesis. Although clear examples of pathogen encoded POPs are currently limited to members of the poxviridae, the human genome likely encodes three POPs (POP1, POP2, and a potential POP3), of which only POP2 is known to prevent NLR:ASC interaction, and three COPs (COP/Pseudo-ICE, INCA, and ICEBERG), initially described for their ability to inhibit caspase-1 activity. Surprisingly, among eukaryotic species POPs and COPs appear to be evolutionarily recent and restricted to higher primates, suggesting strong selective pressures driving their emergence. Despite the importance of understanding the regulation of NLR functions, relatively little attention has been devoted to revealing the biological impact of these intriguing proteins. This review highlights the current state of our understanding of POPs and COPs with attention to protein interaction, functions, evolution, implications for health and disease, and outstanding questions.

          Related collections

          Most cited references61

          • Record: found
          • Abstract: found
          • Article: not found

          Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

          Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection.

            Nod2 activates the NF-kappaB pathway following intracellular stimulation by bacterial products. Recently, mutations in Nod2 have been shown to be associated with Crohn's disease, suggesting a role for bacteria-host interactions in the etiology of this disorder. We show here that Nod2 is a general sensor of peptidoglycan through the recognition of muramyl dipeptide (MDP), the minimal bioactive peptidoglycan motif common to all bacteria. Moreover, the 3020insC frameshift mutation, the most frequent Nod2 variant associated with Crohn's disease patients, fully abrogates Nod2-dependent detection of peptidoglycan and MDP. Together, these results impact on the understanding of Crohn's disease development. Additionally, the characterization of Nod2 as the first pathogen-recognition molecule that detects MDP will help to unravel the well known biological activities of this immunomodulatory compound.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan.

              Although the role of Toll-like receptors in extracellular bacterial sensing has been investigated intensively, intracellular detection of bacteria through Nod molecules remains largely uncharacterized. Here, we show that human Nod1 specifically detects a unique diaminopimelate-containing N-acetylglucosamine-N-acetylmuramic acid (GlcNAc-MurNAc) tripeptide motif found in Gram-negative bacterial peptidoglycan, resulting in activation of the transcription factor NF-kappaB pathway. Moreover, we show that in epithelial cells (which represent the first line of defense against invasive pathogens), Nod1is indispensable for intracellular Gram-negative bacterial sensing.
                Bookmark

                Author and article information

                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                17 September 2013
                2013
                : 4
                : 275
                Affiliations
                [1] 1Center for Immunology and Microbial Disease, Albany Medical College , Albany, NY, USA
                [2] 2Department of Biochemistry, Faculty of Biology, University of Science, Vietnam National University-Ho Chi Minh City , Ho Chi Minh City, Vietnam
                Author notes

                Edited by: Thomas A. Kufer, University of Cologne, Germany

                Reviewed by: Ashley Mansell, Monash Institute of Medical Research, Australia; John P. Vasilakos, 3M Company, USA

                *Correspondence: Jonathan A. Harton, Center for Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, MC-151, Albany, NY 12208, USA e-mail: hartonj@ 123456mail.amc.edu

                This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology.

                Article
                10.3389/fimmu.2013.00275
                3775265
                24062743
                b9b94317-0d93-41fd-9168-7afef7263f88
                Copyright © 2013 Le and Harton.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 June 2013
                : 28 August 2013
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 73, Pages: 10, Words: 8955
                Categories
                Immunology
                Review Article

                Immunology
                pyrin,card,nlr,inflammasome,nf-kappab,inhibitors
                Immunology
                pyrin, card, nlr, inflammasome, nf-kappab, inhibitors

                Comments

                Comment on this article