Signaling Mechanisms Regulating Innate Immune Responses

Abraham, Clara; Vogel, Stefanie N.; Perkins, Darren J.

doi:10.1016/b978-0-12-415847-4.00030-6

Cited by 2 publications

(2 citation statements)

References 199 publications

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“…As mentioned above, p38 MAPK is one of three members of the MAPK protein family, that in response to LPS, induces the expression of proinflammatory cytokines (IL-12, IL-23, TNF-α, IL-6, and IL-1β) through activation of the downstream transcription factor AP-1 ( 31 ). In addition, the MyD88-dependent TLR4/TLR2 induced activation of MAPKs and NF-κB and subsequent proinflammatory response is well characterized ( 3 , 5 , 15 , 31 , 76 ). Interestingly, this inflammatory response is also regulated through the direct interaction of TIRAP with p38 MAPK and PKCδ in LPS-stimulated macrophages ( 30 ) and suggests that TIRAP has multiple functions in the induction of MAPK signaling.…”

Section: Tirap and P38 Mitogen-activated Protein Kinasementioning

confidence: 99%

“…The interleukin-1 receptor-associated kinase (IRAK) family protein kinase consists of four members, IRAK-1, IRAK-2, IRAK-3/M, and IRAK-4 ( 84 ). The sequential activation and recruitment of IRAKs, excluding IRAK-M, in MyD88 dependent signaling is well studied and reported in TLR signaling ( 76 , 85 – 87 ). In the TLR-4-TIRAP-MyD88 mydossome complex, active MyD88 interacts with the N- terminal death domains of IRAK4, triggering a series of phosphorylation events and recruitment of IRAK-1 and IRAK-2, which are required for TRAF-6 ubiquitination, activation, and downstream activation of NF-κB ( 88 , 89 ).…”

Section: Tirap and Interleukin-1 Receptor-associated Kinase-like 2 (Irak-2)mentioning

confidence: 99%

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TIRAP in the Mechanism of Inflammation

et al. 2021

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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.

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Section: Tirap and P38 Mitogen-activated Protein Kinasementioning

confidence: 99%

Section: Tirap and Interleukin-1 Receptor-associated Kinase-like 2 (Irak-2)mentioning

confidence: 99%

TIRAP in the Mechanism of Inflammation

et al. 2021

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TIRAP-mediated activation of p38 MAPK in inflammatory signaling

Rajpoot

Kumar

Zhang

et al. 2022

Sci Rep

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The role of TIRAP (toll/interleukin-1 receptor (TIR) domain-containing adapter protein) in macrophage inflammatory signalling has been significantly evolved since its discovery in 2001 due to its dynamic nature and subcellular localization to regulate multiple signaling through several protein–protein interactions (PPIs). Structural analysis of these interactions can reveal a better understanding of their conformational dynamics and the nature of their binding. Tyrosine phosphorylation in the TIR domain of TIRAP is very critical for its function. In toll-like receptor (TLR) 4/2 signalling, Bruton's tyrosine kinase (BTK) and Protein kinase C delta (PKCδ) are known to phosphorylate the Y86, Y106, Y159, and Y187 of TIRAP which is crucial for the downstream function of MAPKs (mitogen-activated protein kinases) activation. The objective of this study is to understand the interaction of TIRAP with p38 MAPK through molecular docking and identify the importance of TIRAP tyrosine phosphorylation in p38 MAPK interaction. In this structural study, we performed an in-silico molecular docking using HADDOCK 2.4, pyDockWEB, ClusPro 2.0, and ZDOCK 3.0.2 tools to unravel the interaction between TIRAP and p38 MAPK. Further, manual in-silico phosphorylations of TIRAP tyrosines; Y86, Y106, Y159, and Y187 was created in the Discovery Studio tool to study the conformational changes in protein docking and their binding affinities with p38 MAPK in comparison to non-phosphorylated state. Our molecular docking and 500 ns of molecular dynamic (MD) simulation study demonstrates that the Y86 phosphorylation (pY86) in TIRAP is crucial in promoting the higher binding affinity (∆Gbind) with p38 MAPK. The conformational changes due to the tyrosine phosphorylation mainly at the Y86 site pull the TIRAP closer to the active site in the kinase domain of p38 MAPK and plays a significant role at the interface site which is reversed in its dephosphorylated state. The heatmap of interactions between the TIRAP and p38 MAPK after the MD simulation shows that the TIRAP pY86 structure makes the highest number of stable hydrogen bonds with p38 MAPK residues. Our findings may further be validated in an in-vitro system and would be crucial for targeting the TIRAP and p38 MAPK interaction for therapeutic purposes against the chronic inflammatory response and associated diseases.

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Signaling Mechanisms Regulating Innate Immune Responses

Cited by 2 publications

References 199 publications

TIRAP in the Mechanism of Inflammation

TIRAP in the Mechanism of Inflammation

TIRAP-mediated activation of p38 MAPK in inflammatory signaling

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