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.

Toll-Interleukin 1 Receptor (TIR) Domain-Containing Adapter Protein

2012 ◽  
pp. 1884-1884
Author(s):  
João Gonçalves ◽  
Helena Soares ◽  
Norman L. Eberhardt ◽  
Sarah C. R. Lummis ◽  
David R. Soto-Pantoja ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Adapter Protein ◽  
Tir Domain

scholarly journals Targeting Toll-like Receptor (TLR) Signaling by Toll/Interleukin-1 Receptor (TIR) Domain-containing Adapter Protein/MyD88 Adapter-like (TIRAP/Mal)-derived Decoy Peptides

2012 ◽  
Vol 287 (29) ◽  
pp. 24641-24648 ◽  
Author(s):  
Leah A. Couture ◽  
Wenji Piao ◽  
Lisa W. Ru ◽  
Stefanie N. Vogel ◽  
Vladimir Y. Toshchakov
Keyword(s):  
Interleukin 1 ◽  
Adapter Protein ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Tir Domain

New thoughts on the role of the βγ subunit in G protein signal transduction

2000 ◽  
Vol 78 (5) ◽  
pp. 537-550 ◽  
Author(s):  
Barbara Vanderbeld ◽  
Gregory M Kelly
Keyword(s):  
Signal Transduction ◽  
G Protein ◽  
G Proteins ◽  
G Protein Coupled Receptors ◽  
Limited Information ◽  
Α Subunit ◽  
Downstream Effectors ◽  
Receptor Signal ◽  
G Protein Coupled

Heterotrimeric G proteins are involved in numerous biological processes, where they mediate signal transduction from agonist-bound G-protein-coupled receptors to a variety of intracellular effector molecules and ion channels. G proteins consist of two signaling moieties: a GTP-bound α subunit and a βγ heterodimer. The βγ dimer, recently credited as a significant modulator of G-protein-mediated cellular responses, is postulated to be a major determinant of signaling fidelity between G-protein-coupled receptors and downstream effectors. In this review we have focused on the role of βγ signaling and have included examples to demonstrate the heterogeneity in the heterodimer composition and its implications in signaling fidelity. We also present an overview of some of the effectors regulated by βγ and draw attention to the fact that, although G proteins and their associated receptors play an instrumental role in development, there is rather limited information on βγ signaling in embryogenesis.Key words: G protein, βγ subunit, G-protein-coupled receptor, signal transduction, adenylyl cyclase.

Pococurante (Poc): An ENU-Induced Missense Mutation of MyD88 with Selective Effects on TLR Signal Transduction.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 649-649
Author(s):  
Zhengfan Jiang ◽  
Chenglong Li ◽  
Louis Shamel ◽  
Arthur Olson ◽  
Bruce Beutler
Keyword(s):  
Signal Transduction ◽  
Interleukin 1 ◽  
Adaptor Protein ◽  
Structural Diversity ◽  
Lipoteichoic Acid ◽  
Protein Docking ◽  
Structural Basis ◽  
Cpg Dna ◽  
Cpg Dinucleotides ◽  
Tir Domain

Abstract Toll-like receptors (TLRs) are key sensors of the innate immune system, and individual TLRs respond to specific molecules derived from microbes. MyD88 is a Toll/Interleukin-1/Resistance (TIR) domain-containing adaptor protein required for signaling by all TLRs except TLR3. While the structural basis of association between MyD88 and TIR-domain receptors is obscure, MyD88-deficient mice show no responses to bacterial flagellin, peptidoglycan (PGN), lipoteichoic acid (LTA), bacterial lipopeptides such as PAM2CSK4, PAM3CSK4 and R- or S-MALP-2, DNA bearing unmethylated CpG dinucleotides (CpG DNA), or Resiquimod (RSQ). Using germline ENU mutagenesis, we have produced a large number of phenotypic variants that have abnormal TLR signaling. We now report the identification of a new mutation called Pococurante (Poc), originally detected in screening because macrophages from this mouse showed no response to the tri-acylated lipopeptide PAM3CSK4, the di-acylated lipopeptide S-MALP-2, LTA, CpG DNA, RSQ, and a markedly reduced response to LPS: the ligands for TLRs 2/1, 2/6, 9, 7 and 4 respectively. They also had no response to interleukin-1, a cytokine that signals by way of a MyD88-dependent TIR domain receptor. However, Poc mice showed a normal response to PGN, as well as R-MALP-2 and PAM2CSK4 lipopeptides. The latter three ligands are sensed in a TLR2-dependent, MyD88-dependent fashion. The Poc phenotype was ascribed to a point mutation of MyD88 affecting a surface residue (I179N). Because the mutation is discriminatory, permitting MyD88 to carry a signal from some TIR domain receptors but not others, we infer that it resides at the receptor:adaptor signaling interface. A new model of TIR receptor:adaptor interaction is proposed on the basis of docking studies that take account of the Poc phenotype, made using the protein-protein docking program SURFDOCK. We note that S-MALP-2 is dependent upon TLR2/6 heterodimers, while PAM3CSK4 sensing depends upon TLR2/1 heterodimers. Since the Poc mutation forbids detection of both these ligands while it allows detection of PAM2CSK4 and R-MALP-2, it may be inferred that TLR2 signal transduction entails greater structural diversity than was previously supposed. The involvement of TLR2 homodimers, or the incorporation of subunits yet unknown into the receptor complex, cannot be excluded.

The role of the CGRP-receptor component protein (RCP) in adrenomedullin receptor signal transduction

Peptides ◽  
2001 ◽  
Vol 22 (11) ◽  
pp. 1773-1781 ◽  
Author(s):  
Marya A Prado ◽  
Bornadata Evans-Bain ◽  
Kevin R Oliver ◽  
Ian M Dickerson
Keyword(s):  
Signal Transduction ◽  
Cgrp Receptor ◽  
Receptor Signal ◽  
Receptor Component ◽  
Adrenomedullin Receptor ◽  
Component Protein

scholarly journals Suppressor of Cytokine Signaling-3 Inhibits Interleukin-1 Signaling by Targeting the TRAF-6/TAK1 Complex

2006 ◽  
Vol 20 (7) ◽  
pp. 1587-1596 ◽  
Author(s):  
Helle Frobøse ◽  
Sif Groth Rønn ◽  
Peter E. Heding ◽  
Heidi Mendoza ◽  
Philip Cohen ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Interleukin 1 ◽  
Cytokine Signaling ◽  
Nuclear Factor ◽  
Tnf Receptor ◽  
Suppressor Of Cytokine Signaling ◽  
Signaling Complex ◽  
Nuclear Factor Κ B ◽  
Erk Kinase

Abstract IL-1 plays a major role in inflammation and autoimmunity through activation of nuclear factor κ B (NFκB) and MAPKs. Although a great deal is known about the mechanism of activation of NFκB and MAPKs by IL-1, much less is known about the down-regulation of this pathway. Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFκB and the MAPKs JNK and p38, but the mechanism is unknown. We show here that SOCS-3 inhibits NFκB-dependent transcription induced by overexpression of the upstream IL-1 signaling molecules MyD88, IL-1R-activated kinase 1, TNF receptor-associated factor (TRAF)6, and TGFβ-activated kinase (TAK)1, but not when the MAP3K MAPK/ERK kinase kinase-1 is used instead of TAK1, indicating that the target for SOCS-3 is the TRAF6/TAK1 signaling complex. By coimmunoprecipitation, it was shown that SOCS-3 inhibited the association between TRAF6 and TAK1 and that SOCS-3 coimmunoprecipitated with TAK1 and TRAF6. Furthermore, SOCS-3 inhibited the IL-1-induced catalytic activity of TAK1. Because ubiquitination of TRAF6 is required for activation of TAK1, we analyzed the role of SOCS-3 on TRAF6 ubiquitination and found that SOCS-3 inhibited ubiquitin modification of TRAF6. These results indicate that SOCS-3 inhibits IL-1 signal transduction by inhibiting ubiquitination of TRAF6, thus preventing association and activation of TAK1.

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