TLR2 Signaling Pathway Combats Streptococcus Uberis Infection by Inducing Mitochondrial Reactive Oxygen Species Production
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Molecular Mechanism of ACAD9 in Mitochondrial Respiratory Complex 1 Assembly
bioRxiv preprint doi: https://doi.org/10.1101/2021.01.07.425795; this version posted January 9, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Molecular mechanism of ACAD9 in mitochondrial respiratory complex 1 assembly Chuanwu Xia1, Baoying Lou1, Zhuji Fu1, Al-Walid Mohsen2, Jerry Vockley2, and Jung-Ja P. Kim1 1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA 2Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA Abstract ACAD9 belongs to the acyl-CoA dehydrogenase family, which catalyzes the α-β dehydrogenation of fatty acyl-CoA thioesters. Thus, it is involved in fatty acid β-oxidation (FAO). However, it is now known that the primary function of ACAD9 is as an essential chaperone for mitochondrial respiratory complex 1 assembly. ACAD9 interacts with ECSIT and NDUFAF1, forming the mitochondrial complex 1 assembly (MCIA) complex. Although the role of MCIA in the complex 1 assembly pathway is well studied, little is known about the molecular mechanism of the interactions among these three assembly factors. Our current studies reveal that when ECSIT interacts with ACAD9, the flavoenzyme loses the FAD cofactor and consequently loses its FAO activity, demonstrating that the two roles of ACAD9 are not compatible. ACAD9 binds to the carboxy-terminal half (C-ECSIT), and NDUFAF1 binds to the amino-terminal half of ECSIT. Although the binary complex of ACAD9 with ECSIT or with C-ECSIT is unstable and aggregates easily, the ternary complex of ACAD9-ECSIT-NDUFAF1 (i.e., the MCIA complex) is soluble and extremely stable. -
TLR3-Dependent Activation of TLR2 Endogenous Ligands Via the Myd88 Signaling Pathway Augments the Innate Immune Response
cells Article TLR3-Dependent Activation of TLR2 Endogenous Ligands via the MyD88 Signaling Pathway Augments the Innate Immune Response 1 2, 1 3 Hellen S. Teixeira , Jiawei Zhao y, Ethan Kazmierski , Denis F. Kinane and Manjunatha R. Benakanakere 2,* 1 Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19004, USA; [email protected] (H.S.T.); [email protected] (E.K.) 2 Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19004, USA; [email protected] 3 Periodontology Department, Bern Dental School, University of Bern, 3012 Bern, Switzerland; [email protected] * Correspondence: [email protected] Present address: Department of Pathology, Wayne State University School of Medicine, y 541 East Canfield Ave., Scott Hall 9215, Detroit, MI 48201, USA. Received: 30 June 2020; Accepted: 12 August 2020; Published: 17 August 2020 Abstract: The role of the adaptor molecule MyD88 is thought to be independent of Toll-like receptor 3 (TLR3) signaling. In this report, we demonstrate a previously unknown role of MyD88 in TLR3 signaling in inducing endogenous ligands of TLR2 to elicit innate immune responses. Of the various TLR ligands examined, the TLR3-specific ligand polyinosinic:polycytidylic acid (poly I:C), significantly induced TNF production and the upregulation of other TLR transcripts, in particular, TLR2. Accordingly, TLR3 stimulation also led to a significant upregulation of endogenous TLR2 ligands mainly, HMGB1 and Hsp60. By contrast, the silencing of TLR3 significantly downregulated MyD88 and TLR2 gene expression and pro-inflammatory IL1β, TNF, and IL8 secretion. The silencing of MyD88 similarly led to the downregulation of TLR2, IL1β, TNF and IL8, thus suggesting MyD88 / to somehow act downstream of TLR3. -
Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis
biology Review Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis Goncalo Barreto 1,2,* , Mikko Manninen 3 and Kari K. Eklund 1,2,3 1 Department of Rheumatology, Helsinki University and Helsinki University Hospital, 00014 Helsinki, Finland; kari.eklund@hus.fi 2 Translational Immunology Research Program, University of Helsinki, 00014 Helsinki, Finland 3 Orton Research Institute, 00280 Helsinki, Finland; mikko.manninen@orton.fi * Correspondence: goncalo.barreto@helsinki.fi; Tel.: +358-4585-381-10 Received: 24 February 2020; Accepted: 28 March 2020; Published: 30 March 2020 Abstract: Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. In particular, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by alarmins (also known as danger signals) are thought to be involved. Thus, toll-like receptors (TLRs) and their signaling pathways are of particular interest. Recent reports suggest that among the TLR-induced innate immune responses, apoptosis is one of the critical events. Apoptosis is of particular importance, given that chondrocyte death is a dominant feature in OA. This review focuses on the role of TLR signaling in chondrocytes and the role of TLR activation in chondrocyte apoptosis. The functional relevance of TLR and TLR-triggered apoptosis in OA are discussed as well as their relevance as candidates for novel disease-modifying OA drugs (DMOADs). Keywords: osteoarthritis; chondrocytes; toll-like receptors; apoptosis; innate immunity; cartilage 1. Introduction: The Role of Immunity in OA Clinical osteoarthritis (OA) is preceded by a preclinical stage, which, in conjunction with the presence of risk factors and/or other pathological factors, proceeds to the radiographic OA state. -
Dephosphorylating TRAM TRIF-Dependent TLR4 Pathway by Phosphatase PTPN4 Preferentially Inhibits
Phosphatase PTPN4 Preferentially Inhibits TRIF-Dependent TLR4 Pathway by Dephosphorylating TRAM This information is current as Wanwan Huai, Hui Song, Lijuan Wang, Bingqing Li, Jing of September 29, 2021. Zhao, Lihui Han, Chengjiang Gao, Guosheng Jiang, Lining Zhang and Wei Zhao J Immunol published online 30 March 2015 http://www.jimmunol.org/content/early/2015/03/28/jimmun ol.1402183 Downloaded from 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 © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 30, 2015, doi:10.4049/jimmunol.1402183 The Journal of Immunology Phosphatase PTPN4 Preferentially Inhibits TRIF-Dependent TLR4 Pathway by Dephosphorylating TRAM Wanwan Huai,* Hui Song,* Lijuan Wang,† Bingqing Li,‡ Jing Zhao,* Lihui Han,* Chengjiang Gao,* Guosheng Jiang,‡ Lining Zhang,* and Wei Zhao* TLR4 recruits TRIF-related adaptor molecule (TRAM, also known as TICAM2) as a sorting adaptor to facilitate the interaction between TLR4 and TRIF and then initiate TRIF-dependent IRF3 activation. -
Maturation and Is Inhibited by TLR2 Signaling Through TLR4 Promotes
Role of TLR in B Cell Development: Signaling through TLR4 Promotes B Cell Maturation and Is Inhibited by TLR2 This information is current as Elize A. Hayashi, Shizuo Akira and Alberto Nobrega of September 28, 2021. J Immunol 2005; 174:6639-6647; ; doi: 10.4049/jimmunol.174.11.6639 http://www.jimmunol.org/content/174/11/6639 Downloaded from References This article cites 45 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/174/11/6639.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 28, 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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Role of TLR in B Cell Development: Signaling through TLR4 Promotes B Cell Maturation and Is Inhibited by TLR21 Elize A. Hayashi,* Shizuo Akira,† and Alberto Nobrega2* The role of TLR4 in mature B cell activation is well characterized. -
RT² Profiler PCR Array (96-Well Format and 384-Well [4 X 96] Format)
RT² Profiler PCR Array (96-Well Format and 384-Well [4 x 96] Format) Human Toll-Like Receptor Signaling Pathway Cat. no. 330231 PAHS-018ZA For pathway expression analysis Format For use with the following real-time cyclers RT² Profiler PCR Array, Applied Biosystems® models 5700, 7000, 7300, 7500, Format A 7700, 7900HT, ViiA™ 7 (96-well block); Bio-Rad® models iCycler®, iQ™5, MyiQ™, MyiQ2; Bio-Rad/MJ Research Chromo4™; Eppendorf® Mastercycler® ep realplex models 2, 2s, 4, 4s; Stratagene® models Mx3005P®, Mx3000P®; Takara TP-800 RT² Profiler PCR Array, Applied Biosystems models 7500 (Fast block), 7900HT (Fast Format C block), StepOnePlus™, ViiA 7 (Fast block) RT² Profiler PCR Array, Bio-Rad CFX96™; Bio-Rad/MJ Research models DNA Format D Engine Opticon®, DNA Engine Opticon 2; Stratagene Mx4000® RT² Profiler PCR Array, Applied Biosystems models 7900HT (384-well block), ViiA 7 Format E (384-well block); Bio-Rad CFX384™ RT² Profiler PCR Array, Roche® LightCycler® 480 (96-well block) Format F RT² Profiler PCR Array, Roche LightCycler 480 (384-well block) Format G RT² Profiler PCR Array, Fluidigm® BioMark™ Format H Sample & Assay Technologies Description The Human Toll-Like Receptor (TLR) Signaling Pathway RT² Profiler PCR Array profiles the expression of 84 genes central to TLR-mediated signal transduction and innate immunity. The TLR family of pattern recognition receptors (PRRs) detects a wide range of bacteria, viruses, fungi and parasites via pathogen-associated molecular patterns (PAMPs). Each receptor binds to specific ligands, initiates a tailored innate immune response to the specific class of pathogen, and activates the adaptive immune response. -
TLR Signaling Pathways
Seminars in Immunology 16 (2004) 3–9 TLR signaling pathways Kiyoshi Takeda, Shizuo Akira∗ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and ERATO, Japan Science and Technology Corporation, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan Abstract Toll-like receptors (TLRs) have been established to play an essential role in the activation of innate immunity by recognizing spe- cific patterns of microbial components. TLR signaling pathways arise from intracytoplasmic TIR domains, which are conserved among all TLRs. Recent accumulating evidence has demonstrated that TIR domain-containing adaptors, such as MyD88, TIRAP, and TRIF, modulate TLR signaling pathways. MyD88 is essential for the induction of inflammatory cytokines triggered by all TLRs. TIRAP is specifically involved in the MyD88-dependent pathway via TLR2 and TLR4, whereas TRIF is implicated in the TLR3- and TLR4-mediated MyD88-independent pathway. Thus, TIR domain-containing adaptors provide specificity of TLR signaling. © 2003 Elsevier Ltd. All rights reserved. Keywords: TLR; Innate immunity; Signal transduction; TIR domain 1. Introduction 2. Toll-like receptors Toll receptor was originally identified in Drosophila as an A mammalian homologue of Drosophila Toll receptor essential receptor for the establishment of the dorso-ventral (now termed TLR4) was shown to induce the expression pattern in developing embryos [1]. In 1996, Hoffmann and of genes involved in inflammatory responses [3]. In addi- colleagues demonstrated that Toll-mutant flies were highly tion, a mutation in the Tlr4 gene was identified in mouse susceptible to fungal infection [2]. This study made us strains that were hyporesponsive to lipopolysaccharide [4]. aware that the immune system, particularly the innate im- Since then, Toll receptors in mammals have been a major mune system, has a skilful means of detecting invasion by focus in the immunology field. -
Original Article Investigation for the Roles of TLR2, TLR9 and Th17/Treg in the Pathogenesis of Infectious Mononucleosis
Int J Clin Exp Med 2017;10(10):14946-14953 www.ijcem.com /ISSN:1940-5901/IJCEM0037168 Original Article Investigation for the roles of TLR2, TLR9 and Th17/Treg in the pathogenesis of infectious mononucleosis Aning Gao1, Yawang Shao2 1Department of Pediatrics, The Central Hospital of Xianyang, Shaanxi Province, China; 2Department of Pediatrics, The First People’ s Hospital of Xianyang, Xianyang City 712000, Shaanxi Province, China Received August 3, 2016; Accepted August 12, 2017; Epub October 15, 2017; Published October 30, 2017 Abstract: Infectious mononucleosis (IM) is caused by Epstein-Barr virus (EBV) infection. Toll-like receptor 2 (TLR2) has most recognized ligands, and is possibly direct receptor for anti-EBV. EBV can also activate TLR9 on B cells for inducing anti-viral response. T helper cell 17 (Th17) can promote inflammation by secreting IL-17, and is possibly involved in IM pathogenesis. Regulatory T cell (Treg) is a T cell sub-population with immune suppression. The previ- ous study has indicated insufficient Treg cell immunity for acute IM onset. This study thus aims to investigate the TLR2, TL9, Th17 and CD4+CD25+Treg cell expression, and to explore its potential role in IM. A total of 98 acute IM children and 76 IM children at recovery period were recruited in our hospital, in parallel with 52 healthy children. The qRT-PCR and western blot assay were used to test mRNA or protein expressions of TLR2 and TLR9, respectively. Flow cytometry was used to test percentage of Th17 and CD4+CD25+Foxp3+T cell in total CD4+T cells. ELISA was employed for detecting serum levels of IL-17, IL-22, IL-19 and TGF-β. -
TLR4 Signalling
RESEA r CH HIGHLIGHTS INNATE IMMUNITY TLR4 signalling Toll-like receptor 4 (TLR4) is unique plasma membrane. Now, a study from sufficient to allow TRAM to localize among TLRs in its ability to activate Ruslan Medzhitov’s laboratory shows specifically to endosomes. These 20 two distinct signalling pathways that the two signalling pathways amino acids constitute a bipartite — one pathway is activated by the are induced sequentially and that localization domain — consisting of adaptors TIRAP (Toll/interleukin-1- the TRAM–TRIF pathway is only a myristoylation motif (the first 7 receptor (TIR)-domain-containing operational from early endosomes amino acids) and a polybasic domain adaptor protein) and MyD88, following endocytosis of TLR4. — that is commonly found in other which leads to the induction of The authors found it puzzling proteins that shuttle between the pro‑inflammatory cytokines, and that TLR4 is the only known TLR plasma membrane and endosomes. the second pathway is activated by capable of inducing the production Mutational analysis showed that the the adaptors TRIF (TIR-domain- of type I interferons from the plasma myristoylation motif is necessary containing adaptor protein inducing membrane so they decided to take for endosomal localization but interferon‑β) and TRAM (TRIF- a closer look at TLR4 signalling. both parts of the bipartite motif related adaptor molecule), which First, they assessed the subcellular are required for plasma-membrane leads to the induction of type I inter- localization of tagged TLR4 and found targeting. A TRAM transgene of ferons. Until now, it had been believed that it localized to both the plasma which the protein product resided that these two signalling pathways membrane and endosomal vesicles. -
Ecsit Is Required for Bmp Signaling and Mesoderm Formation During Mouse Embryogenesis
Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis Changchun Xiao,1 Jae-hyuck Shim,1,6 Michael Klüppel,5,6 Samuel Shao-Min Zhang,3,6 Chen Dong,1,7 Richard A. Flavell,1 Xin-Yuan Fu,3 Jeffrey L. Wrana,5 Brigid L.M. Hogan,4 and Sankar Ghosh1,2,8 1Section of Immunobiology, 2Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, and 3Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA; 4Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA; 5Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada Bone morphogenetic proteins (Bmps) are members of the transforming growth factor  (TGF) superfamily that play critical roles during mouse embryogenesis. Signaling by Bmp receptors is mediated mainly by Smad proteins. In this study, we show that a targeted null mutation of Ecsit, encoding a signaling intermediate of the Toll pathway, leads to reduced cell proliferation, altered epiblast patterning, impairment of mesoderm formation, and embryonic lethality at embryonic day 7.5 (E7.5), phenotypes that mimic the Bmp receptor type1a (Bmpr1a) null mutant. In addition, specific Bmp target gene expression is abolished in the absence of Ecsit. Biochemical analysis demonstrates that Ecsit associates constitutively with Smad4 and associates with Smad1 in a Bmp-inducible manner. Together with Smad1 and Smad4, Ecsit binds to the promoter of specific Bmp target genes. Finally, knock-down of Ecsit with Ecsit-specific short hairpin RNA inhibits both Bmp and Toll signaling. -
Adjuvant Effect of the Novel TLR1/TLR2 Agonist Diprovocim Synergizes with Anti–PD-L1 to Eliminate Melanoma in Mice
Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti–PD-L1 to eliminate melanoma in mice Ying Wanga, Lijing Sua, Matthew D. Morinb, Brian T. Jonesb, Yuto Mifuneb, Hexin Shia, Kuan-wen Wanga, Xiaoming Zhana, Aijie Liua, Jianhui Wanga, Xiaohong Lia, Miao Tanga, Sara Ludwiga, Sara Hildebranda, Kejin Zhouc,d, Daniel J. Siegwartc,d, Eva Marie Y. Morescoa, Hong Zhanga, Dale L. Bogerb, and Bruce Beutlera,1 aCenter for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390; bDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; cSimmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; and dDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 Edited by Dennis A. Carson, University of California, San Diego, La Jolla, CA, and approved July 2, 2018 (received for review June 28, 2018) Successful cancer immunotherapy entails activation of innate immune (MyD88,TRIF,TRAM,andMAL),kinases, and ubiquitin ligases receptors to promote dendritic cell (DC) maturation, antigen pre- to activate NF-κB and IRFs (12–14). These and other transcription sentation, up-regulation of costimulatory molecules, and cytokine factors induce the expression of thousands of genes that carry out secretion, leading to activation of tumor antigen-specific cytotoxic the innate immune response (15). Several nucleotide-based adju- T lymphocytes (CTLs). Here we screened a synthetic library of 100,000 vants such as TLR3 agonist poly I:C (9), TLR9 agonist CpG (16), compounds for innate immune activators using TNF production by and STING agonist cGAMP (6) have been reported to improve THP-1 cells as a readout. -
Mitochondrial Medicine in the Omics Era
Mitochondrial Medicine in the Omics Era Joyeeta Rahman1 and Shamima Rahman1,2* 1 Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health and 2 Metabolic Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK *Correspondence to: Professor Shamima Rahman Mitochondrial Research Group Genetics and Genomic Medicine UCL Great Ormond Street Institute of Child Health London WC1N 1EH, UK. Telephone: +44 (0)2079052608 [email protected] Keywords: Mitochondrial disease, OXPHOS, signalling, omics, genomics, transcriptomics, proteomics, metabolomics, mitochondrial stress response, treatment 1 Abstract Mitochondria are dynamic bioenergetic organelles whose maintenance requires ~1500 proteins from two genomes. Mutations in either the mitochondrial or nuclear genome can disrupt a plethora of cellular metabolic and homeostatic functions. Mitochondrial diseases represent one the most common and severe groups of inherited genetic disorders, characterised by clinical, biochemical, and genetic heterogeneity, diagnostic odysseys, and lack of curative therapies. This review aims to discuss recent advances in mitochondrial biology and medicine arising from widespread utilisation of high-throughput omics technologies, and also includes a broad discussion of emerging therapies for mitochondrial disease. New insights into both bioenergetic and biosynthetic mitochondrial functionalities have expedited the genetic diagnosis of primary mitochondrial disorders, and identified novel mitochondrial pathomechanisms and new targets