Toll/interleukin-1 receptor (TIR) domain-mediated cellular signaling pathways

Narayanan, Kannan Badri; Park, Hyun Ho

doi:10.1007/s10495-014-1073-1

Cited by 149 publications

(124 citation statements)

References 108 publications

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“…For example, TLRs couple ligand binding to conformational changes that are transduced through the plasma membrane to TIR domains in the cytosol and activate signaling pathways (37). The cytosolic adaptor TRIF/TICAM1 uses a mechanism wherein the N-terminal domain folds back onto the TIR domain to hide essential effector residues in the unstructured region adjacent to the TIR domain (30).…”

Section: The Sarm1 Tir Domain Is a Conserved Executioner Of Neuronalmentioning

confidence: 99%

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

Summers

Gibson

DiAntonio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

116

123

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Axon injury in response to trauma or disease stimulates a selfdestruction 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.A xon degeneration in response to injury or disease is a hallmark of neurological disorders of the peripheral and central nervous systems. Akin to programmed cell death pathways, such as apoptosis, axon injury in response to disease or trauma stimulates a local signaling cascade that executes destruction of the injured axon segment (1). Despite growing attention, the molecular details of this prodegenerative cascade are still unclear. A more substantial understanding of the molecular factors that participate in this axon destructive process will likely provide new therapeutic strategies for peripheral neuropathies and other neurodegenerative conditions.Genetic screens in invertebrate and vertebrate model systems identified the Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) as a conserved, fundamental executioner of pathological axon destruction (2, 3). After nerve injury, SARM1 is required for the precipitous loss of the metabolite NAD + (4). Augmenting NAD + biosynthetic pathways protects injured axons from degeneration, suggesting this step is crucial in axonal breakdown (5, 6). In addition to local axon degeneration, SARM1 promotes neuronal cell death in response to mitochondrial toxins, oxygen gluc...

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Section: The Sarm1 Tir Domain Is a Conserved Executioner Of Neuronalmentioning

confidence: 99%

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

Summers

Gibson

DiAntonio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

116

123

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“…[26][27][28] In the TRIF-dependent pathway, the TLR4 myeloid differentiation protein 2 (MD2)-LPS complex is internalized and transferred to early endosomes via TRIF-related adaptor molecule (TRAM), where TRAM, TRIF, TRAF3, TRAF6, and other adaptor proteins are recruited to activate NF-kB and interferon responses. [29][30][31] Activation of NF-kB, MAPK, and interferon results in enhanced inflammatory cytokine responses and induction of DCs function.…”

Section: Discussionmentioning

confidence: 99%

Repulsive guidance molecule a blockade exerts the immunoregulatory function in DCs stimulated with ABP and LPS

Gao

Zhai

et al. 2016

Human Vaccines & Immunotherapeutics

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Repulsive guidance molecule a (RGMa) is an axonal guidance molecule that has recently found to exert function in immune system. This study evaluated the function of RGMa in modulation of dendritic cells (DCs) function stimulated with Achyranthes bidentata polysaccharide (ABP) and lipopolysaccharide (LPS) using a RGMa-neutralizing antibody. Compared with the Control-IgG/ABP and Control-IgG/LPS groups, DCs in the Anti-RGMa/ABP and Anti-RGMa/LPS groups 1) showed small, round cells with a few cell processes and organelles, and many pinocytotic vesicles; 2) had decreased MHC II, CD86, CD80, and CD40 expression; 3) displayed the decreased IL-12p70, IL-1b and TNF-a levels and increased IL-10 secretion; 4) had a high percentage of FITC-dextran uptake; and 5) displayed a reduced ability to drive T cell proliferation and reinforced T cell polarization toward a Th2 cytokine pattern. We conclude that DCs treated with RGMa-neutralizing antibodies present with tolerogenic and immunoregulatory characteristics, which provides new insights into further understanding of the function of RGMa.

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“…TIR domain-containing adapter-inducing beta interferon (TRIF) is an adapter molecule that transduces intracellular signaling upon recognition of Gram-negative bacteria by Toll-like receptor 4 (TLR4) or double-stranded-RNA (dsRNA) viruses by TLR3 (6). Our previous findings regarding the unique role of innate TRIF signaling in intestinal defense against Gram-negative bacteria along with the evidence that TRIF is required for induction of costimulatory molecules and major histocompatibility complex (MHC) class II antigens suggest that TRIF may play an important role at the innate and adaptive interface (7)(8)(9).…”

Section: H Ost Defense Against Bacterial Pathogens Utilizes Innate Phmentioning

confidence: 99%

TIR Domain-Containing Adapter-Inducing Beta Interferon (TRIF) Mediates Immunological Memory against Bacterial Pathogens

et al. 2015

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H ost defense against bacterial pathogens utilizes innate phagocytes and CD4 ϩ T cells, and successful interaction between innate and adaptive immunity establishes immunological memory. A fine interplay between innate and adaptive immune responses is necessary to eliminate pathogenic bacteria from the gastrointestinal tract without destruction of normal flora, mucosal barrier function, and gut homeostasis. However, the mechanisms regulating the interactions between innate and adaptive immunity during enteric bacterial infections have yet to be fully determined.Innate immunity covers immediate host defense against pathogens in a non-antigen-specific manner while the body is conducting initiation and calibration of adaptive immunity. In this system, pathogen-experienced antigen-presenting cells (APCs) induce differentiation of cytotoxic and helper T (Th) cells that form pathogen-specific acquired immunity. Multiple types of Th cells are generated in local lymphoid tissues during infection, while Th17 cell generation is dominant in the intestine (1). The antibacterial properties of Th17 cells have been observed in lung infections with Gram-negative extracellular bacteria (2, 3). In the intestine, however, the role of Th17 cells in host resistance to bacterial infection seems to be more complicated, as they may work as innate immune cells (4, 5). Although the importance of memory CD4 ϩ T cells in host defense against bacterial infection has been well established, the exact extent of coverage by memory Th17 cells has yet to be determined.TIR domain-containing adapter-inducing beta interferon (TRIF) is an adapter molecule that transduces intracellular signaling upon recognition of Gram-negative bacteria by Toll-like receptor 4 (TLR4) or double-stranded-RNA (dsRNA) viruses by TLR3 (6). Our previous findings regarding the unique role of innate TRIF signaling in intestinal defense against Gram-negative bacteria along with the evidence that TRIF is required for induction of costimulatory molecules and major histocompatibility complex (MHC) class II antigens suggest that TRIF may play an important role at the innate and adaptive interface (7-9).In this study, we sought to determine the role of TRIF signaling in establishing immunological memory as well as in conferring protective immunity against Gram-negative bacterial infection. We show that TRIF-deficient (Trif LPS2 ) mice failed to demonstrate increased resistance to secondary infection. TRIF deficiency resulted in the enhanced generation and maintenance of CD4 ϩ central memory T (T CM ) cells that expressed interleukin 17 (IL-17) in an antigen-specific manner. These IL-17 ϩ CD4 ϩ T cells facilitated neutrophil influx to the primary infection site and conferred on macrophages (Ms) full bactericidal function to eliminate Gram-negative pathogens only when TRIF signaling was present in innate immune cells. Therefore, our results highlight the importance of TRIF in regulating the balance between innate and adaptive immune responses to develop immune resistance to reinfecti...

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Toll/interleukin-1 receptor (TIR) domain-mediated cellular signaling pathways

Cited by 149 publications

References 108 publications

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

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

Repulsive guidance molecule a blockade exerts the immunoregulatory function in DCs stimulated with ABP and LPS

TIR Domain-Containing Adapter-Inducing Beta Interferon (TRIF) Mediates Immunological Memory against Bacterial Pathogens

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Toll/interleukin-1 receptor (TIR) domain-mediated cellular signaling pathways

Cited by 149 publications

References 108 publications

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

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

Repulsive guidance molecule a blockade exerts the immunoregulatory function in DCs stimulated with ABP and LPS

TIR Domain-Containing Adapter-Inducing Beta Interferon (TRIF) Mediates Immunological Memory against Bacterial Pathogens

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

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