NOD2: Activation During Bacterial and Viral Infections, Polymorphisms
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The Expression of NOD2, NLRP3 and NLRC5 and Renal Injury in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Wang et al. J Transl Med (2019) 17:197 https://doi.org/10.1186/s12967-019-1949-5 Journal of Translational Medicine RESEARCH Open Access The expression of NOD2, NLRP3 and NLRC5 and renal injury in anti-neutrophil cytoplasmic antibody-associated vasculitis Luo‑Yi Wang1,2,3, Xiao‑Jing Sun1,2,3, Min Chen1,2,3* and Ming‑Hui Zhao1,2,3,4 Abstract Background: Nucleotide‑binding oligomerization domain (NOD)‑like receptors (NLRs) are intracellular sensors of pathogens and molecules from damaged cells to regulate the infammatory response in the innate immune system. Emerging evidences suggested a potential role of NLRs in anti‑neutrophil cytoplasmic antibody (ANCA)‑associated vasculitis (AAV). This study aimed to investigate the expression of nucleotide‑binding oligomerization domain con‑ taining protein 2 (NOD2), NOD‑like receptor family pyrin domain containing 3 (NLRP3) and NOD‑like receptor family CARD domain containing 5 (NLRC5) in kidneys of AAV patients, and further explored their associations with clinical and pathological parameters. Methods: Thirty‑four AAV patients in active stage were recruited. Their renal specimens were processed with immu‑ nohistochemistry to assess the expression of three NLRs, and with double immunofuorescence to detect NLRs on intrinsic and infltrating cells. Analysis of gene expression was also adopted in cultured human podocytes. The associa‑ tions between expression of NLRs and clinicopathological parameters were analyzed. Results: The expression of NOD2, NLRP3 and NLRC5 was signifcantly higher in kidneys from AAV patients than those from normal controls, minimal change disease or class IV lupus nephritis. These NLRs co‑localized with podocytes and infltrating infammatory cells. -
Genetic Diagnosis in First Or Second Trimester Pregnancy Loss Using Exome Sequencing: a Systematic Review of Human Essential Genes
Journal of Assisted Reproduction and Genetics (2019) 36:1539–1548 https://doi.org/10.1007/s10815-019-01499-6 REVIEW Genetic diagnosis in first or second trimester pregnancy loss using exome sequencing: a systematic review of human essential genes Sarah M. Robbins1,2 & Matthew A. Thimm3 & David Valle1 & Angie C. Jelin4 Received: 18 December 2018 /Accepted: 29 May 2019 /Published online: 4 July 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose Non-aneuploid recurrent pregnancy loss (RPL) affects approximately 100,000 pregnancies worldwide annually. Exome sequencing (ES) may help uncover the genetic etiology of RPL and, more generally, pregnancy loss as a whole. Previous studies have attempted to predict the genes that, when disrupted, may cause human embryonic lethality. However, predictions by these early studies rarely point to the same genes. Case reports of pathogenic variants identified in RPL cases offer another clue. We evaluated known genetic etiologies of RPL identified by ES. Methods We gathered primary research articles from PubMed and Embase involving case reports of RPL reporting variants identified by ES. Two authors independently reviewed all articles for eligibility and extracted data based on predetermined criteria. Preliminary and amended analysis isolated 380 articles; 15 met all inclusion criteria. Results These 15 articles described 74 families with 279 reported RPLs with 34 candidate pathogenic variants in 19 genes (NOP14, FOXP3, APAF1, CASP9, CHRNA1, NLRP5, MMP10, FGA, FLT1, EPAS1, IDO2, STIL, DYNC2H1, IFT122, PA DI6, CAPS, MUSK, NLRP2, NLRP7) and 26 variants of unknown significance in 25 genes. These genes cluster in four essential pathways: (1) gene expression, (2) embryonic development, (3) mitosis and cell cycle progression, and (4) inflammation and immunity. -
Genetic Variation in Pattern-Recognition Receptors and Association with Leprosy 145
DOI: 10.5772/intechopen.73871 ProvisionalChapter chapter 8 Genetic Variation inin Pattern-RecognitionPattern-Recognition ReceptorsReceptors and and Association withwith LeprosyLeprosy Karina Talita de Oliveira Santana JorgeJorge andand Frederico Marianetti SorianiSoriani Additional information isis available atat thethe endend ofof thethe chapterchapter http://dx.doi.org/10.5772/intechopen.73871 Abstract Mycobacterium leprae is a highly infectious and low pathogenic microorganism that is the causal agent of leprosy. The differences in vulnerability to leprosy, the spectral immune response, and the clinical manifestations of this disease are related to different genetic backgrounds among individuals. In this sense, genetic variants, especially in genes related to mycobacteria recognition and host immune response, may be key factors to explain individual susceptibility and resistance to leprosy and their conditions. In this chapter, studies regarding association of genetic variants in pattern-recognition receptors (PRRs) and leprosy will be reviewed revealing the importance of molecules such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in leprosy initiation and maintenance. Keywords: polymorphisms, pattern-recognition receptors, mycobacterium leprae, leprosy 1. Introduction Leprosy is caused by Mycobacterium leprae, which is an intracellular bacterium with high infectivity and low pathogenicity. It means that there are a large number of people exposed to this pathogen; however, the majority of them are naturally resistant. On the other hand, some people develop leprosy once challenged with M. leprae. The people who develop disease may present different clinical forms of leprosy. Some of them develop a localized disease, named tuberculoid leprosy, with a strong host response, which does not avoid development of nerve injury and physical disabilities. -
Cytotoxic T Cells Class I- Dependent Lymphocyte Killing by NLRC5 Deficiency Selectively Impairs
The Journal of Immunology NLRC5 Deficiency Selectively Impairs MHC Class I- Dependent Lymphocyte Killing by Cytotoxic T Cells Francesco Staehli,* Kristina Ludigs,* Leonhard X. Heinz,† Queralt Seguı´n-Este´vez,‡ Isabel Ferrero,x Marion Braun,x Kate Schroder,{ Manuele Rebsamen,† Aubry Tardivel,* Chantal Mattmann,* H. Robson MacDonald,x Pedro Romero,x Walter Reith,‡ Greta Guarda,*,1 and Ju¨rg Tschopp*,1,2 Nucleotide-binding oligomerization domain-like receptors (NLRs) are intracellular proteins involved in innate-driven inflamma- tory responses. The function of the family member NLR caspase recruitment domain containing protein 5 (NLRC5) remains a matter of debate, particularly with respect to NF-kB activation, type I IFN, and MHC I expression. To address the role of NLRC5, we generated Nlrc5-deficient mice (Nlrc5D/D). In this article we show that these animals exhibit slightly decreased CD8+ T cell percentages, a phenotype compatible with deregulated MHC I expression. Of interest, NLRC5 ablation only mildly affected MHC I expression on APCs and, accordingly, Nlrc5D/D macrophages efficiently primed CD8+ T cells. In contrast, NLRC5 deficiency dramatically impaired basal expression of MHC I in T, NKT, and NK lymphocytes. NLRC5 was sufficient to induce MHC I expression in a human lymphoid cell line, requiring both caspase recruitment and LRR domains. Moreover, endogenous NLRC5 localized to the nucleus and occupied the proximal promoter region of H-2 genes. Consistent with downregulated MHC I expression, the elimination of Nlrc5D/D lymphocytes by cytotoxic T cells was markedly reduced and, in addition, we observed low NLRC5 expression in several murine and human lymphoid-derived tumor cell lines. -
Post-Transcriptional Inhibition of Luciferase Reporter Assays
THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 287, NO. 34, pp. 28705–28716, August 17, 2012 © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Post-transcriptional Inhibition of Luciferase Reporter Assays by the Nod-like Receptor Proteins NLRX1 and NLRC3* Received for publication, December 12, 2011, and in revised form, June 18, 2012 Published, JBC Papers in Press, June 20, 2012, DOI 10.1074/jbc.M111.333146 Arthur Ling‡1,2, Fraser Soares‡1,2, David O. Croitoru‡1,3, Ivan Tattoli‡§, Leticia A. M. Carneiro‡4, Michele Boniotto¶, Szilvia Benko‡5, Dana J. Philpott§, and Stephen E. Girardin‡6 From the Departments of ‡Laboratory Medicine and Pathobiology and §Immunology, University of Toronto, Toronto M6G 2T6, Canada, and the ¶Modulation of Innate Immune Response, INSERM U1012, Paris South University School of Medicine, 63, rue Gabriel Peri, 94276 Le Kremlin-Bicêtre, France Background: A number of Nod-like receptors (NLRs) have been shown to inhibit signal transduction pathways using luciferase reporter assays (LRAs). Results: Overexpression of NLRX1 and NLRC3 results in nonspecific post-transcriptional inhibition of LRAs. Conclusion: LRAs are not a reliable technique to assess the inhibitory function of NLRs. Downloaded from Significance: The inhibitory role of NLRs on specific signal transduction pathways needs to be reevaluated. Luciferase reporter assays (LRAs) are widely used to assess the Nod-like receptors (NLRs)7 represent an important class of activity of specific signal transduction pathways. Although pow- intracellular pattern recognition molecules (PRMs), which are erful, rapid and convenient, this technique can also generate implicated in the detection and response to microbe- and dan- www.jbc.org artifactual results, as revealed for instance in the case of high ger-associated molecular patterns (MAMPs and DAMPs), throughput screens of inhibitory molecules. -
NOD-Like Receptors in the Eye: Uncovering Its Role in Diabetic Retinopathy
International Journal of Molecular Sciences Review NOD-like Receptors in the Eye: Uncovering Its Role in Diabetic Retinopathy Rayne R. Lim 1,2,3, Margaret E. Wieser 1, Rama R. Ganga 4, Veluchamy A. Barathi 5, Rajamani Lakshminarayanan 5 , Rajiv R. Mohan 1,2,3,6, Dean P. Hainsworth 6 and Shyam S. Chaurasia 1,2,3,* 1 Ocular Immunology and Angiogenesis Lab, University of Missouri, Columbia, MO 652011, USA; [email protected] (R.R.L.); [email protected] (M.E.W.); [email protected] (R.R.M.) 2 Department of Biomedical Sciences, University of Missouri, Columbia, MO 652011, USA 3 Ophthalmology, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 652011, USA 4 Surgery, University of Missouri, Columbia, MO 652011, USA; [email protected] 5 Singapore Eye Research Institute, Singapore 169856, Singapore; [email protected] (V.A.B.); [email protected] (R.L.) 6 Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 652011, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-573-882-3207 Received: 9 December 2019; Accepted: 27 January 2020; Published: 30 January 2020 Abstract: Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM). International Diabetic Federations (IDF) estimates up to 629 million people with DM by the year 2045 worldwide. Nearly 50% of DM patients will show evidence of diabetic-related eye problems. Therapeutic interventions for DR are limited and mostly involve surgical intervention at the late-stages of the disease. The lack of early-stage diagnostic tools and therapies, especially in DR, demands a better understanding of the biological processes involved in the etiology of disease progression. -
ATP-Binding and Hydrolysis in Inflammasome Activation
molecules Review ATP-Binding and Hydrolysis in Inflammasome Activation Christina F. Sandall, Bjoern K. Ziehr and Justin A. MacDonald * Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada; [email protected] (C.F.S.); [email protected] (B.K.Z.) * Correspondence: [email protected]; Tel.: +1-403-210-8433 Academic Editor: Massimo Bertinaria Received: 15 September 2020; Accepted: 3 October 2020; Published: 7 October 2020 Abstract: The prototypical model for NOD-like receptor (NLR) inflammasome assembly includes nucleotide-dependent activation of the NLR downstream of pathogen- or danger-associated molecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomeric platforms that lie upstream of inflammatory responses associated with innate immunity. As members of the STAND ATPases, the NLRs are generally thought to share a similar model of ATP-dependent activation and effect. However, recent observations have challenged this paradigm to reveal novel and complex biochemical processes to discern NLRs from other STAND proteins. In this review, we highlight past findings that identify the regulatory importance of conserved ATP-binding and hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explore recent breakthroughs that generate connections between NLR protein structure and function. Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectives on the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations of NLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctions in nucleotide-binding domain topology with occupancy of ATP or ADP that are in turn disseminated on to the global protein structure. -
Inflammasome Activation and Regulation
Zheng et al. Cell Discovery (2020) 6:36 Cell Discovery https://doi.org/10.1038/s41421-020-0167-x www.nature.com/celldisc REVIEW ARTICLE Open Access Inflammasome activation and regulation: toward a better understanding of complex mechanisms Danping Zheng1,2,TimurLiwinski1,3 and Eran Elinav 1,4 Abstract Inflammasomes are cytoplasmic multiprotein complexes comprising a sensor protein, inflammatory caspases, and in some but not all cases an adapter protein connecting the two. They can be activated by a repertoire of endogenous and exogenous stimuli, leading to enzymatic activation of canonical caspase-1, noncanonical caspase-11 (or the equivalent caspase-4 and caspase-5 in humans) or caspase-8, resulting in secretion of IL-1β and IL-18, as well as apoptotic and pyroptotic cell death. Appropriate inflammasome activation is vital for the host to cope with foreign pathogens or tissue damage, while aberrant inflammasome activation can cause uncontrolled tissue responses that may contribute to various diseases, including autoinflammatory disorders, cardiometabolic diseases, cancer and neurodegenerative diseases. Therefore, it is imperative to maintain a fine balance between inflammasome activation and inhibition, which requires a fine-tuned regulation of inflammasome assembly and effector function. Recently, a growing body of studies have been focusing on delineating the structural and molecular mechanisms underlying the regulation of inflammasome signaling. In the present review, we summarize the most recent advances and remaining challenges in understanding the ordered inflammasome assembly and activation upon sensing of diverse stimuli, as well as the tight regulations of these processes. Furthermore, we review recent progress and challenges in translating inflammasome research into therapeutic tools, aimed at modifying inflammasome-regulated human diseases. -
Blau Syndrome Polymorphisms in NOD2 Identify Nucleotide Hydrolysis and Helical Domain 1 As Signalling Regulators ⇑ Rhiannon Parkhouse A, Joseph P
FEBS Letters 588 (2014) 3382–3389 journal homepage: www.FEBSLetters.org Blau syndrome polymorphisms in NOD2 identify nucleotide hydrolysis and helical domain 1 as signalling regulators ⇑ Rhiannon Parkhouse a, Joseph P. Boyle a,b, Tom P. Monie a,b, a Department of Biochemistry, University of Cambridge, Cambridge, UK b Department of Veterinary Medicine, University of Cambridge, Cambridge, UK article info abstract Article history: Understanding how single nucleotide polymorphisms (SNPs) lead to disease at a molecular level Received 10 June 2014 provides a starting point for improved therapeutic intervention. SNPs in the innate immune recep- Revised 23 July 2014 tor nucleotide oligomerisation domain 2 (NOD2) can cause the inflammatory disorders Blau Syn- Accepted 23 July 2014 drome (BS) and early onset sarcoidosis (EOS) through receptor hyperactivation. Here, we show Available online 2 August 2014 that these polymorphisms cluster into two primary locations: the ATP/Mg2+-binding site and helical Edited by Renee Tsolis domain 1. Polymorphisms in these two locations may consequently dysregulate ATP hydrolysis and NOD2 autoinhibition, respectively. Complementary mutations in NOD1 did not mirror the NOD2 phenotype, which indicates that NOD1 and NOD2 are activated and regulated by distinct methods. Keywords: Nucleotide-binding, leucine-rich repeat Ó 2014 The Authors. Published by Elsevier B.V. on behalf of the Federation of European Biochemical containing receptor Societies. This is an open access article under the CC BY license (http://creativecommons.org/licenses/ -
The Landscape of Genomic Imprinting Across Diverse Adult Human Tissues
Downloaded from genome.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Research The landscape of genomic imprinting across diverse adult human tissues Yael Baran,1 Meena Subramaniam,2 Anne Biton,2 Taru Tukiainen,3,4 Emily K. Tsang,5,6 Manuel A. Rivas,7 Matti Pirinen,8 Maria Gutierrez-Arcelus,9 Kevin S. Smith,5,10 Kim R. Kukurba,5,10 Rui Zhang,10 Celeste Eng,2 Dara G. Torgerson,2 Cydney Urbanek,11 the GTEx Consortium, Jin Billy Li,10 Jose R. Rodriguez-Santana,12 Esteban G. Burchard,2,13 Max A. Seibold,11,14,15 Daniel G. MacArthur,3,4,16 Stephen B. Montgomery,5,10 Noah A. Zaitlen,2,19 and Tuuli Lappalainen17,18,19 1The Blavatnik School of Computer Science, Tel-Aviv University, Tel Aviv 69978, Israel; 2Department of Medicine, University of California San Francisco, San Francisco, California 94158, USA; 3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; 4Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA; 5Department of Pathology, Stanford University, Stanford, California 94305, USA; 6Biomedical Informatics Program, Stanford University, Stanford, California 94305, USA; 7Wellcome Trust Center for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7BN, United Kingdom; 8Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; 9Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland; -
NLRP2 and FAF1 Deficiency Blocks Early Embryogenesis in the Mouse
REPRODUCTIONRESEARCH NLRP2 and FAF1 deficiency blocks early embryogenesis in the mouse Hui Peng1,*, Haijun Liu2,*, Fang Liu1, Yuyun Gao1, Jing Chen1, Jianchao Huo1, Jinglin Han1, Tianfang Xiao1 and Wenchang Zhang1 1College of Animal Science, Fujian Agriculture and Forestry University, Fujian, Fuzhou, People’s Republic of China and 2Tianjin Institute of Animal Science and Veterinary Medicine, Tianjin, People’s Republic of China Correspondence should be addressed to W Zhang; Email: [email protected] *(H Peng and H Liu contributed equally to this work) Abstract Nlrp2 is a maternal effect gene specifically expressed by mouse ovaries; deletion of this gene from zygotes is known to result in early embryonic arrest. In the present study, we identified FAF1 protein as a specific binding partner of the NLRP2 protein in both mouse oocytes and preimplantation embryos. In addition to early embryos, both Faf1 mRNA and protein were detected in multiple tissues. NLRP2 and FAF1 proteins were co-localized to both the cytoplasm and nucleus during the development of oocytes and preimplantation embryos. Co-immunoprecipitation assays were used to confirm the specific interaction between NLRP2 and FAF1 proteins. Knockdown of the Nlrp2 or Faf1 gene in zygotes interfered with the formation of a NLRP2–FAF1 complex and led to developmental arrest during early embryogenesis. We therefore conclude that NLRP2 interacts with FAF1 under normal physiological conditions and that this interaction is probably essential for the successful development of cleavage-stage mouse embryos. Our data therefore indicated a potential role for NLRP2 in regulating early embryo development in the mouse. Reproduction (2017) 154 245–251 Introduction (Peng et al. -
Coincidental Loss of DOCK8 Function in NLRP10-Deficient and C3H/Hej Mice Results in Defective Dendritic Cell Migration
Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration Jayendra Kumar Krishnaswamya,b,1, Arpita Singha,b,1, Uthaman Gowthamana,b, Renee Wua,b, Pavane Gorrepatia,b, Manuela Sales Nascimentoa,b, Antonia Gallmana,b, Dong Liua,b, Anne Marie Rhebergenb, Samuele Calabroa,b, Lan Xua,b, Patricia Ranneya,b, Anuj Srivastavac, Matthew Ransond, James D. Gorhamd, Zachary McCawe, Steven R. Kleebergere, Leonhard X. Heinzf, André C. Müllerf, Keiryn L. Bennettf, Giulio Superti-Furgaf, Jorge Henao-Mejiag, Fayyaz S. Sutterwalah, Adam Williamsi, Richard A. Flavellb,j,2, and Stephanie C. Eisenbartha,b,2 Departments of aLaboratory Medicine and bImmunobiology and jHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520; cComputational Sciences, The Jackson Laboratory, Bar Harbor, ME 04609; dDepartment of Pathology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755; eNational Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; fCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; gInstitute for Immunology, Departments of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; hInflammation Program, Department of Internal Medicine, University of Iowa, Iowa City, IA 52241; and iThe Jackson Laboratory for Genomic Medicine, Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06032 Contributed by Richard A. Flavell, January 28, 2015 (sent for review December 23, 2014; reviewed by Matthew L. Albert and Thirumala-Devi Kanneganti) Dendritic cells (DCs) are the primary leukocytes responsible for NLRP10 is the only NOD-like receptor (NLR) without a leu- priming T cells.