TIRAP in the Mechanism of Inflammation

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.

Toll-Like Receptors (TLRs), NOD-Like Receptors (NLRs), and RIG-I-Like Receptors (RLRs) in Innate Immunity. TLRs, NLRs, and RLRs Ligands as Immunotherapeutic Agents for Hematopoietic Diseases

“…TRIF is attached to TLR3 or TLR4 and promotes an alternative signaling pathway leading to activation of IRF3, NF-kB, and MAPKs, causing increased synthesis of IFN I and proinflammatory cytokines. TRAM is connected to TLR4 as a bridge between TRIF and TLR4 and TLR3 connects directly to TRIF [63,64]. Depending on the adaptor attached, TLRs signaling pathways have been divided into two pathways, MyD88-dependent and TRIF-dependent.…”

A Prognostic Signature Consisting of Pyroptosis-Related Genes and SCAF11 for Predicting Immune Response in Breast Cancer

“…Nucleotide binding/leucine-rich repeat (NLR) family caspase-activation and recruitment domain (CARD) domain containing 4 (NLRC4) inflammasome activates CASP1 after exposure to intracellular bacteria, such as S. typhimurium ( 35 ), and NLRC4 activation is critical in defense against enteric pathogens and systemic pathogens ( 36 ). The toll/interleukin-1 receptor (TIR) domain containing adaptor protein (TIRAP) is an adapter molecule which has an elaborate role in inflammatory signaling pathways and host immune signaling ( 37 ). TNF (tumor necrosis factor) is a proinflammatory cytokine generated by various cells in response to a wide variety of immune stimuli and stress conditions ( 38 ).…”

The expanding roles of neuronal nitric oxide synthase (NOS1)

“…SOCS1 is mainly responsible for the proteasomal degradation of the TIRAP protein, which eventually disrupts TLR-mediated inflammatory signaling and inactivate TF NF-κB. However, the inhibition of SOCS1 by NOS1-derived NO activated NF-κB mediated elaboration of pro-inflammatory cytokines ( Baig et al, 2015 ; Rajpoot et al, 2021 ). Therefore, it is conceivable that the complete ablation of NOS1 could alter signaling pathways at several cellular and molecular levels in the tissue microenvironment.…”