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      NOD-Like Receptors in Infection, Immunity, and Diseases

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          Abstract

          Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are pattern-recognition receptors similar to toll-like receptors (TLRs). While TLRs are transmembrane receptors, NLRs are cytoplasmic receptors that play a crucial role in the innate immune response by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Based on their N-terminal domain, NLRs are divided into four subfamilies: NLRA, NLRB, NLRC, and NLRP. NLRs can also be divided into four broad functional categories: inflammasome assembly, signaling transduction, transcription activation, and autophagy. In addition to recognizing PAMPs and DAMPs, NLRs act as a key regulator of apoptosis and early development. Therefore, there are significant associations between NLRs and various diseases related to infection and immunity. NLR studies have recently begun to unveil the roles of NLRs in diseases such as gout, cryopyrin-associated periodic fever syndromes, and Crohn's disease. As these new associations between NRLs and diseases may improve our understanding of disease pathogenesis and lead to new approaches for the prevention and treatment of such diseases, NLRs are becoming increasingly relevant to clinicians. In this review, we provide a concise overview of NLRs and their role in infection, immunity, and disease, particularly from clinical perspectives.

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          Most cited references72

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          The role of Atg proteins in autophagosome formation.

          Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.
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            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.
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              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.
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                Author and article information

                Journal
                Yonsei Med J
                Yonsei Med. J
                YMJ
                Yonsei Medical Journal
                Yonsei University College of Medicine
                0513-5796
                1976-2437
                01 January 2016
                30 November 2015
                : 57
                : 1
                : 5-14
                Affiliations
                [1 ]Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.
                [2 ]Department of Microbiology, Yonsei University College of Medicine, Seoul, Korea.
                [3 ]Brain Korea 21 PLUS for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
                [4 ]Severance Biomedical Science Institute and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea.
                [5 ]Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
                [6 ]Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
                Author notes
                Corresponding author: Dr. Moon H. Nahm, Departments of Pathology and Microbiology, University of Alabama at Birmingham, Bevill Building, Room 614 (BBRB 614), 845 19th Street South, Birmingham, AL 35294, USA. Tel: 1-205-934-0163, Fax: 1-205-975-2149, nahm@ 123456uab.edu
                Article
                10.3349/ymj.2016.57.1.5
                4696971
                26632377
                36549d11-438d-4978-9d26-8ec91ed0665d
                © Copyright: Yonsei University College of Medicine 2016

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 07 July 2015
                Categories
                Review Article

                Medicine
                innate immunity,pattern recognition receptors,nod-like receptors,inflammasomes
                Medicine
                innate immunity, pattern recognition receptors, nod-like receptors, inflammasomes

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