TIRAP in the Mechanism of Inflammation.

Sajjan Rajpoot,Uzma Saqib,Rachel Ibbott,Teresa L M Thurston,Dongfang Liu,Mirza S Baig,Kishore K Wary

doi:10.3389/fimmu.2021.697588

Abstract

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.

Highlights

TIRAP, known as Myeloid differentiation factor 88 (MyD88)-adaptor Like (MAL), is an adapter molecule associated with receptor-mediated activation of host immune signaling [1, 2]
10 TIRAP-BRUTON’S TYROSINE KINASE (BTK) Proinflammatory In stimulated TLR4/2 pathways, the interaction with BTK is crucial for TIRAP activation via its tyrosine response phosphorylation at Toll-interleukin-1 Receptor (TIR) domain leading to downstream nuclear factor kB (NF-kB) and AP-1 activation
With the critical molecules poised to become activated at the membrane, BTK-mediated TIRAP phosphorylation and activation, followed by degradation of phospho-TIRAP, results in a rapid yet balanced inflammatory response, avoiding prolonged TLR4 or TLR2 signaling that would otherwise result in chronic inflammation and associated diseases [23]

Summary

Introduction

TIRAP, known as MyD88-adaptor Like (MAL), is an adapter molecule associated with receptor-mediated activation of host immune signaling [1, 2]. Phosphorylation of the cytoplasmic tail of the TLR4 TIR domain at Y674 and Y680 and phosphorylation of TIRAP tyrosine residues at positions 86, 106, 159, and 187 by BTK are required for TLR4-TIRAP-MyD88 interaction and activation of NF-kB and MAPK (mitogen-activated protein kinase) signaling leading to proinflammatory responses (Figure 2) [17, 26, 45, 46]. 10 TIRAP-BTK Proinflammatory In stimulated TLR4/2 pathways, the interaction with BTK is crucial for TIRAP activation via its tyrosine response phosphorylation at TIR domain leading to downstream NF-kB and AP-1 activation

Results

Conclusion