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 SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation

2016 ◽  
Vol 113 (41) ◽  
pp. E6271-E6280 ◽  
Author(s):  
Daniel W. Summers ◽  
Daniel A. Gibson ◽  
Aaron DiAntonio ◽  
Jeffrey Milbrandt
Keyword(s):  
Innate Immune ◽  
Axon Degeneration ◽  
Physical Interaction ◽  
Structural Elements ◽  
Axon Injury ◽  
Tir Domain ◽  
Fundamental Properties ◽  
Innate Immune Signaling ◽  
Evolutionarily Conserved ◽  
Tir Domains

Axon injury in response to trauma or disease stimulates a self-destruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling. In contrast, dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD+ and induces neuronal destruction. This activity is unique to the SARM1 TIR domain, yet the structural elements that enable this activity are unknown. In this study, we identify fundamental properties of the SARM1 TIR domain that promote NAD+ loss and axon degeneration. Dimerization of the TIR domain from the Caenorhabditis elegans SARM1 ortholog TIR-1 leads to NAD+ loss and neuronal death, indicating these activities are an evolutionarily conserved feature of SARM1 function. Detailed analysis of sequence homology identifies canonical TIR motifs as well as a SARM1-specific (SS) loop that are required for NAD+ loss and axon degeneration. Furthermore, we identify a residue in the SARM1 BB loop that is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1, suggesting that SARM1 function requires multidomain interactions. Indeed, we identify a physical interaction between the autoinhibitory N terminus and the TIR domain of SARM1, revealing a previously unrecognized direct connection between these domains that we propose mediates autoinhibition and activation upon injury.

scholarly journals Indoleamine 2,3-Dioxygenase 1 Is a Lung-Specific Innate Immune Defense Mechanism That Inhibits Growth of Francisella tularensis Tryptophan Auxotrophs

2010 ◽  
Vol 78 (6) ◽  
pp. 2723-2733 ◽  
Author(s):  
Kaitian Peng ◽  
Denise M. Monack
Keyword(s):  
Francisella Tularensis ◽  
Defense Mechanisms ◽  
Defense Mechanism ◽  
Immune Defense ◽  
The Body ◽  
Innate Immune ◽  
Microbial Pathogens ◽  
Immune Mechanisms ◽  
Indoleamine 2,3 Dioxygenase ◽  
Organ Specific

ABSTRACT Upon microbial challenge, organs at various anatomic sites of the body employ different innate immune mechanisms to defend against potential infections. Accordingly, microbial pathogens evolved to subvert these organ-specific host immune mechanisms to survive and grow in infected organs. Francisella tularensis is a bacterium capable of infecting multiple organs and thus encounters a myriad of organ-specific defense mechanisms. This suggests that F. tularensis may possess specific factors that aid in evasion of these innate immune defenses. We carried out a microarray-based, negative-selection screen in an intranasal model of Francisella novicida infection to identify Francisella genes that contribute to bacterial growth specifically in the lungs of mice. Genes in the bacterial tryptophan biosynthetic pathway were identified as being important for F. novicida growth specifically in the lungs. In addition, a host tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase 1 (IDO1), is induced specifically in the lungs of mice infected with F. novicida or Streptococcus pneumoniae. Furthermore, the attenuation of F. novicida tryptophan mutant bacteria was rescued in the lungs of IDO1−/− mice. IDO1 is a lung-specific innate immune mechanism that controls pulmonary Francisella infections.

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 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 TIRAP in the Mechanism of Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Sajjan Rajpoot ◽  
Kishore K. Wary ◽  
Rachel Ibbott ◽  
Dongfang Liu ◽  
Uzma Saqib ◽  
...  
Keyword(s):  
Immune Responses ◽  
Protein Interactions ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Adaptor Protein ◽  
Intracellular Signalling ◽  
Tir Domain ◽  
Signalling Molecules ◽  
Inflammatory Conditions ◽  
Signalling Molecule

The Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP) represents a key intracellular signalling molecule regulating diverse immune responses. Its capacity to function as an adaptor molecule has been widely investigated in relation to Toll-like Receptor (TLR)-mediated innate immune signalling. Since the discovery of TIRAP in 2001, initial studies were mainly focused on its role as an adaptor protein that couples Myeloid differentiation factor 88 (MyD88) with TLRs, to activate MyD88-dependent TLRs signalling. Subsequent studies delineated TIRAP’s role as a transducer of signalling events through its interaction with non-TLR signalling mediators. Indeed, the ability of TIRAP to interact with an array of intracellular signalling mediators suggests its central role in various immune responses. Therefore, continued studies that elucidate the molecular basis of various TIRAP-protein interactions and how they affect the signalling magnitude, should provide key information on the inflammatory disease mechanisms. This review summarizes the TIRAP recruitment to activated receptors and discusses the mechanism of interactions in relation to the signalling that precede acute and chronic inflammatory diseases. Furthermore, we highlighted the significance of TIRAP-TIR domain containing binding sites for several intracellular inflammatory signalling molecules. Collectively, we discuss the importance of the TIR domain in TIRAP as a key interface involved in protein interactions which could hence serve as a therapeutic target to dampen the extent of acute and chronic inflammatory conditions.

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 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.

The role of MyD88-like adapters in Toll-like receptor signal transduction

2003 ◽  
Vol 31 (3) ◽  
pp. 643-647 ◽  
Author(s):  
L.A.J. O'Neill
Keyword(s):  
Signal Transduction ◽  
Interleukin 1 ◽  
Adapter Proteins ◽  
Adapter Protein ◽  
Tir Domain ◽  
Receptor Signal ◽  
The Subject ◽  
Tir Domains ◽  
Tlr Signalling

Signal-transduction pathways activated by Toll-like receptors (TLRs) have been the subject of intense investigation because of the key role played by TLRs in the recognition and elimination of microbes. Signalling is initiated by a domain termed the Toll/interleukin-1 (IL-1) receptor (TIR) domain that occurs on the cytosolic face of TLRs. This recruits, via homotypic interactions, adapter proteins that contain TIR domains. Three such adapter proteins have been discovered to date, and have been named MyD88, Mal [MyD88 adapter-like; also known as TIRAP (TIR domain-containing adapter protein)] and Trif (TIR-domain-containing adapter inducing interferon-β). Differences are emerging between TLRs in terms of which adapter is recruited by which TLR. This may lead to specificities in TLR signalling, with pathways being triggered that are specific for the elimination of the invading microbe. However, signals that separate Mal from MyD88 have yet to emerge, although biochemical differences between the two proteins imply that each will have a specific function.

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