scholarly journals Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4

2003 ◽  
Vol 197 (2) ◽  
pp. 263-268 ◽  
Author(s):  
Kimberly Burns ◽  
Sophie Janssens ◽  
Brian Brissoni ◽  
Natalia Olivos ◽  
Rudi Beyaert ◽  
...  
Keyword(s):  
Short Form ◽  
Interleukin 1 ◽  
Negative Regulator ◽  
Death Domain ◽  
Innate Immune Responses ◽  
Tir Domain ◽  
Intermediate Domain ◽  
Alternatively Spliced ◽  
Tir Domains ◽  
Multiple Signaling

Toll-like receptors (TLRs) and members of the proinflammatory interleukin 1 receptor (IL-1R) family are dependent on the presence of MyD88 for efficient signal transduction. The bipartite nature of MyD88 (N-terminal death domain [DD] and COOH-terminal Toll/IL-1 receptor [TIR] domain) allows it to link the TIR domain of IL-1R/TLR with the DD of the Ser/Thr kinase termed IL-1R–associated kinase (IRAK)-1. This triggers IRAK-1 phosphorylation and in turn the activation of multiple signaling cascades such as activation of the transcription factor nuclear factor (NF)-κB. In contrast, expression of MyD88 short (MyD88s), an alternatively spliced form of MyD88 that lacks only the short intermediate domain separating the DD and TIR domains, leads to a shutdown of IL-1/lipopolysaccharide-induced NF-κB activation. Here, we provide the molecular explanation for this difference. MyD88 but not MyD88s strongly interacts with IRAK-4, a newly identified kinase essential for IL-1R/TLR signaling. In the presence of MyD88s, IRAK-1 is not phosphorylated and neither activates NF-κB nor is ubiquitinated. Thus, MyD88s acts as a negative regulator of IL-1R/TLR/MyD88-triggered signals, leading to a transcriptionally controlled negative regulation of innate immune responses.

scholarly journals Heterologous Expression and Assembly of Human TLR Signaling Components in Saccharomyces cerevisiae

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1737
Author(s):  
Julia María Coronas-Serna ◽  
Elba del Val ◽  
Jonathan C. Kagan ◽  
María Molina ◽  
Víctor J. Cid
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Interleukin 1 ◽  
Death Domain ◽  
Tlr Signaling ◽  
Tir Domain ◽  
Protein Protein Interaction ◽  
Interaction Domains ◽  
Membrane Bound ◽  
Tir Domains

Toll-like receptor (TLR) signaling is key to detect pathogens and initiating inflammation. Ligand recognition triggers the assembly of supramolecular organizing centers (SMOCs) consisting of large complexes composed of multiple subunits. Building such signaling hubs relies on Toll Interleukin-1 Receptor (TIR) and Death Domain (DD) protein-protein interaction domains. We have expressed TIR domain-containing components of the human myddosome (TIRAP and MyD88) and triffosome (TRAM and TRIF) SMOCs in Saccharomyces cerevisiae, as a platform for their study. Interactions between the TLR4 TIR domain, TIRAP, and MyD88 were recapitulated in yeast. Human TIRAP decorated the yeast plasma membrane (PM), except for the bud neck, whereas MyD88 was found at cytoplasmic spots, which were consistent with endoplasmic reticulum (ER)-mitochondria junctions, as evidenced by co-localization with Mmm1 and Mdm34, components of the ER and Mitochondria Encounter Structures (ERMES). The formation of MyD88-TIRAP foci at the yeast PM was reinforced by co-expression of a membrane-bound TLR4 TIR domain. Mutations in essential residues of their TIR domains aborted MyD88 recruitment by TIRAP, but their respective subcellular localizations were unaltered. TRAM and TRIF, however, did not co-localize in yeast. TRAM assembled long PM-bound filaments that were disrupted by co-expression of the TLR4 TIR domain. Our results evidence that the yeast model can be exploited to study the interactions and subcellular localization of human SMOC components in vivo.

scholarly journals TIR domains of plant immune receptors are 2',3'-cAMP/cGMP synthetases mediating cell death

2021 ◽  
Author(s):  
Dongli Yu ◽  
Wen Song ◽  
Eddie Yong Jun Tan ◽  
Li Liu ◽  
Yu Cao ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Interleukin 1 ◽  
Structural Data ◽  
Negative Regulator ◽  
Synthetase Activity ◽  
Leucine Rich Repeat ◽  
Tir Domain ◽  
Immune Receptors ◽  
Tir Domains

2′,3′-cAMP is a positional isomer of the well-established second messenger 3′,5′-cAMP, but little is known on the biology of this noncanonical cyclic nucleotide monophosphate (cNMP). Toll/interleukin-1 receptor (TIR) domains of nucleotide-binding leucine-rich repeat (NLR) immune receptors have NADase function necessary but insufficient to activate plant immune responses. Here we show that plant TIR proteins, besides being NADases, act as 2′,3′-cAMP/cGMP synthetases by hydrolyzing RNA/DNA. Structural data shows that a TIR domain adopts distinct oligomers with dual and exclusive enzymatic activity. Mutations specifically disrupting the synthetase activity abrogate TIR-mediated cell death in Nicotiana benthamiana, supporting an important role for these cNMPs in TIR signaling. Furthermore, the Arabidopsis negative regulator of TIR-NLR signaling, NUDT7 displays 2′,3′-cAMP/cGMP but not 3′,5′-cAMP/cGMP phosphodiesterase activity and suppresses cell death activity of TIRs in N. benthamiana. Our study identifies a novel family of 2′,3′-cAMP/cGMP synthetase and establishes a role for the noncanonical cNMPs in plant immune responses.

scholarly journals Modulation of microtubule dynamics by a TIR domain protein from the intracellular pathogen Brucella melitensis

2011 ◽  
Vol 439 (1) ◽  
pp. 79-83 ◽  
Author(s):  
Girish K. Radhakrishnan ◽  
Jerome S. Harms ◽  
Gary A. Splitter
Keyword(s):  
Brucella Melitensis ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Microtubule Dynamics ◽  
Innate Immune Responses ◽  
Tir Domain ◽  
Microtubule Stabilization ◽  
Loop Region ◽  
Microtubule Formation ◽  
Domain Protein

TIR (Toll/interleukin-1 receptor) domain-containing proteins play a crucial role in innate immunity in eukaryotes. Brucella is a highly infectious intracellular bacterium that encodes a TIR domain protein (TcpB) to subvert host innate immune responses to establish a beneficial niche for pathogenesis. TcpB inhibits NF-κB (nuclear factor κB) activation and pro-inflammatory cytokine secretions mediated by TLR (Toll-like receptor) 2 and TLR4. In the present study, we have demonstrated that TcpB modulates microtubule dynamics by acting as a stabilization factor. TcpB increased the rate of nucleation as well as the polymerization phases of microtubule formation in a similar manner to paclitaxel. TcpB could efficiently inhibit nocodazole- or cold-induced microtubule disassembly. Microtubule stabilization by TcpB is attributed to the BB-loop region of the TIR domain, and a point mutation affected the microtubule stabilization as well as the TLR-suppression properties of TcpB.

scholarly journals Peptide-mediated Interference of TIR Domain Dimerization in MyD88 Inhibits Interleukin-1-dependent Activation of NF-κB

2005 ◽  
Vol 280 (16) ◽  
pp. 15809-15814 ◽  
Author(s):  
Maria Loiarro ◽  
Claudio Sette ◽  
Grazia Gallo ◽  
Andrea Ciacci ◽  
Nicola Fantò ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Cell System ◽  
Tir Domain ◽  
Loop Region ◽  
Good Target ◽  
A Cell ◽  
Tir Domains ◽  
Myeloid Differentiation Factor

Myeloid differentiation factor 88 (MyD88) plays a crucial role in the signaling pathways triggered by interleukin (IL)-1 and Toll-like receptors in several steps of innate host defense. A crucial event in this signaling pathway is represented by dimerization of MyD88, which allows the recruitment of downstream kinases like IRAK-1 and IRAK-4. Herein, we have investigated the function of the Toll/IL-1 receptor (TIR) domain in MyD88 homodimerization in cell-free andin vitroexperimental settings by using epta-peptides that mimic the BB-loop region of the conserved TIR domain of different proteins. By using a pull-down assay with purified glutathioneS-transferase-MyD88 TIR or co-immunoprecipitation experiments, we found that epta-peptides derived from the TIR domain of MyD88 and IL-18R are the most effective in inhibiting homodimerization with either the isolated TIR or full-length MyD88. Moreover, we demonstrated that a cell permeable analog of MyD88 epta-peptide inhibits homodimerization of MyD88 TIR domains in anin vitrocell system and significantly reduces IL-1 signaling, as assayed by activation of the downstream transcription factor NF-κB. Our results indicate that the BB-loop in TIR domain of MyD88 is a good target for specific inhibition of MyD88-mediated signalingin vivo.

scholarly journals Structure of the activated ROQ1 resistosome directly recognizing the pathogen effector XopQ

Science ◽  
2020 ◽  
Vol 370 (6521) ◽  
pp. eabd9993 ◽  
Author(s):  
Raoul Martin ◽  
Tiancong Qi ◽  
Haibo Zhang ◽  
Furong Liu ◽  
Miles King ◽  
...  
Keyword(s):  
Active Site ◽  
Nicotiana Benthamiana ◽  
Interleukin 1 ◽  
Leucine Rich Repeat ◽  
Tir Domain ◽  
Pathogen Effectors ◽  
Cryo Electron Microscopy ◽  
Pathogen Effector ◽  
Tir Domains ◽  
Direct Recognition

Plants and animals detect pathogen infection using intracellular nucleotide-binding leucine-rich repeat receptors (NLRs) that directly or indirectly recognize pathogen effectors and activate an immune response. How effector sensing triggers NLR activation remains poorly understood. Here we describe the 3.8-angstrom-resolution cryo–electron microscopy structure of the activated ROQ1 (recognition of XopQ 1), an NLR native to Nicotiana benthamiana with a Toll-like interleukin-1 receptor (TIR) domain bound to the Xanthomonaseuvesicatoria effector XopQ (Xanthomonas outer protein Q). ROQ1 directly binds to both the predicted active site and surface residues of XopQ while forming a tetrameric resistosome that brings together the TIR domains for downstream immune signaling. Our results suggest a mechanism for the direct recognition of effectors by NLRs leading to the oligomerization-dependent activation of a plant resistosome and signaling by the TIR domain.

scholarly journals Vaccinia virus protein A46R targets multiple Toll-like–interleukin-1 receptor adaptors and contributes to virulence

2005 ◽  
Vol 201 (6) ◽  
pp. 1007-1018 ◽  
Author(s):  
Julianne Stack ◽  
Ismar R. Haga ◽  
Martina Schröder ◽  
Nathan W. Bartlett ◽  
Geraldine Maloney ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Virus Protein ◽  
Innate Defense ◽  
Tir Domain ◽  
Mitogen Activated Protein ◽  
Key Aspects ◽  
Tir Domains ◽  
Myeloid Differentiation Factor

Viral immune evasion strategies target key aspects of the host antiviral response. Recently, it has been recognized that Toll-like receptors (TLRs) have a role in innate defense against viruses. Here, we define the function of the vaccinia virus (VV) protein A46R and show it inhibits intracellular signalling by a range of TLRs. TLR signalling is triggered by homotypic interactions between the Toll-like–interleukin-1 resistance (TIR) domains of the receptors and adaptor molecules. A46R contains a TIR domain and is the only viral TIR domain–containing protein identified to date. We demonstrate that A46R targets the host TIR adaptors myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like, TIR domain–containing adaptor inducing IFN-β (TRIF), and the TRIF-related adaptor molecule and thereby interferes with downstream activation of mitogen-activated protein kinases and nuclear factor κB. TRIF mediates activation of interferon (IFN) regulatory factor 3 (IRF3) and induction of IFN-β by TLR3 and TLR4 and suppresses VV replication in macrophages. Here, A46R disrupted TRIF-induced IRF3 activation and induction of the TRIF-dependent gene regulated on activation, normal T cell expressed and secreted. Furthermore, we show that A46R is functionally distinct from another described VV TLR inhibitor, A52R. Importantly, VV lacking the A46R gene was attenuated in a murine intranasal model, demonstrating the importance of A46R for VV virulence.

scholarly journals Structure of the activated Roq1 resistosome directly recognizing the pathogen effector XopQ

2020 ◽  
Author(s):  
Raoul Martin ◽  
Tiancong Qi ◽  
Haibo Zhang ◽  
Furong Liu ◽  
Miles King ◽  
...  
Keyword(s):  
Immune Response ◽  
Active Site ◽  
Interleukin 1 ◽  
Leucine Rich Repeat ◽  
Tir Domain ◽  
Pathogen Effectors ◽  
Cryo Electron Microscopy ◽  
Pathogen Effector ◽  
Tir Domains ◽  
Direct Recognition

AbstractPlants and animals detect pathogen infection via intracellular nucleotide-binding leucine-rich repeat receptors (NLRs) that directly or indirectly recognize pathogen effectors and activate an immune response. How effector sensing triggers NLR activation remains poorly understood. Here we describe the 3.8 Å resolution cryo-electron microscopy structure of the activated Roq1, an NLR native to Nicotiana benthamiana with a Toll-like interleukin-1 receptor (TIR) domain, bound to the Xanthomonas effector XopQ. Roq1 directly binds to both the predicted active site and surface residues of XopQ while forming a tetrameric resistosome that brings together the TIR domains for downstream immune signaling. Our results suggest a mechanism for the direct recognition of effectors by NLRs leading to the oligomerization-dependent activation of a plant resistosome and signaling by the TIR domain.One Sentence SummaryVisualization of an activated plant immune receptor that triggers the immune response upon pathogen recognition.

scholarly journals Inhibitory Role of an Aeromonas hydrophila TIR Domain Effector in Antibacterial Immunity by Targeting TLR Signaling Complexes in Zebrafish

2021 ◽  
Vol 12 ◽  
Author(s):  
Huai-ping Tang ◽  
Chen Huang ◽  
Chong-bin Hu ◽  
Hao Li ◽  
Tong Shao ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Aeromonas Hydrophila ◽  
Protein Complexes ◽  
Interleukin 1 ◽  
Tumor Necrosis Factor Receptor ◽  
Therapeutic Interventions ◽  
Death Domain ◽  
Tir Domain ◽  
Myeloid Differentiation Factor

The Toll/interleukin-1 receptor (TIR) domain is a structural unit responsible for the assembly of signal protein complexes in Toll-like receptor (TLR) and interleukin-1 receptor signaling pathways. TIR domain homologs are found in a considerable number of bacteria and enhance bacterial infection and survival in host organisms. However, whether TIR domain homologs exist in Aeromonas hydrophila, a ubiquitous waterborne bacterium in aquatic environments, remains poorly understood. In this study, a TIR domain protein (TcpAh) was identified from A. hydrophila JBN2301. TIR domain of TcpAh is highly homologous to the counterpart domains in TLRs and myeloid differentiation factor 88 (MyD88). The zebrafish infected with mutant A. hydrophila with tcpAh deletion had a remarkably lower mortality than those infected with the wild-type strain. This result suggests that TcpAh is a crucial virulence factor for A. hydrophila infection. TcpAh exhibited a strong ability to associate with MyD88, tumor necrosis factor receptor-associated factor 3 (TRAF3) and TRAF-associated NF-κB activator-binding kinase 1 (TBK1) in TIR–TIR, TIR–Death domain (DD), and other alternative interactions. This finding suggests that TcpAh extensively interferes with MyD88 and TIR domain-containing adapter inducing interferon (IFN)-β (TRIF) signaling pathways downstream of TLRs. Consequently, CD80/86 expression was suppressed by TcpAh via attenuating TLR-stimulated NF-κB activation, which ultimately led to the impairment of the major costimulatory signal essential for the initiation of adaptive humoral immunity against A. hydrophila infection. We believe that this study is the first to show a previously unrecognized mechanism underlying A. hydrophila evades from host antibacterial defense by intervening CD80/86 signal, which bridges innate and adaptive immunity. The mechanism will benefit the development of therapeutic interventions for A. hydrophila infection and septicemia by targeting TcpAh homologs.

scholarly journals The SARM1 TIR NADase: Mechanistic Similarities to Bacterial Phage Defense and Toxin-Antitoxin Systems

2021 ◽  
Vol 12 ◽  
Author(s):  
Aaron DiAntonio ◽  
Jeffrey Milbrandt ◽  
Matthew D. Figley
Keyword(s):  
Defense Mechanisms ◽  
Interleukin 1 ◽  
Innate Immune ◽  
Activation Mechanism ◽  
Bacterial Toxin ◽  
Axon Degeneration ◽  
Tir Domain ◽  
Immune Mechanisms ◽  
Signalling Molecules ◽  
Tir Domains

The Toll/interleukin-1 receptor (TIR) domain is the signature signalling motif of innate immunity, with essential roles in innate immune signalling in bacteria, plants, and animals. TIR domains canonically function as scaffolds, with stimulus-dependent multimerization generating binding sites for signalling molecules such as kinases and ligases that activate downstream immune mechanisms. Recent studies have dramatically expanded our understanding of the TIR domain, demonstrating that the primordial function of the TIR domain is to metabolize NAD+. Mammalian SARM1, the central executioner of pathological axon degeneration, is the founding member of the TIR-domain class of NAD+ hydrolases. This unexpected NADase activity of TIR domains is evolutionarily conserved, with archaeal, bacterial, and plant TIR domains all sharing this catalytic function. Moreover, this enzymatic activity is essential for the innate immune function of these proteins. These evolutionary relationships suggest a link between SARM1 and ancient self-defense mechanisms that has only been strengthened by the recent discovery of the SARM1 activation mechanism which, we will argue, is strikingly similar to bacterial toxin-antitoxin systems. In this brief review we will describe the regulation and function of SARM1 in programmed axon self-destruction, and highlight the parallels between the SARM1 axon degeneration pathway and bacterial innate immune mechanisms.

scholarly journals Structural Evolution of TIR-Domain Signalosomes

2021 ◽  
Vol 12 ◽  
Author(s):  
Surekha Nimma ◽  
Weixi Gu ◽  
Natsumi Maruta ◽  
Yan Li ◽  
Mengqi Pan ◽  
...  
Keyword(s):  
Cell Death ◽  
Interleukin 1 ◽  
Structural Evolution ◽  
Functional Roles ◽  
Tir Domain ◽  
Cell Death Pathways ◽  
System A ◽  
Essential Components ◽  
Self Association ◽  
Tir Domains

TIR (Toll/interleukin-1 receptor/resistance protein) domains are cytoplasmic domains widely found in animals and plants, where they are essential components of the innate immune system. A key feature of TIR-domain function in signaling is weak and transient self-association and association with other TIR domains. An additional new role of TIR domains as catalytic enzymes has been established with the recent discovery of NAD+-nucleosidase activity by several TIR domains, mostly involved in cell-death pathways. Although self-association of TIR domains is necessary in both cases, the functional specificity of TIR domains is related in part to the nature of the TIR : TIR interactions in the respective signalosomes. Here, we review the well-studied TIR domain-containing proteins involved in eukaryotic immunity, focusing on the structures, interactions and their corresponding functional roles. Structurally, the signalosomes fall into two separate groups, the scaffold and enzyme TIR-domain assemblies, both of which feature open-ended complexes with two strands of TIR domains, but differ in the orientation of the two strands. We compare and contrast how TIR domains assemble and signal through distinct scaffolding and enzymatic roles, ultimately leading to distinct cellular innate-immunity and cell-death outcomes.

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