Phosphatases in toll-like receptors signaling: the unfairly-forgotten

Lannoy, Valérie; Côté-Biron, Anthony; Asselin, Claude; Rivard, Nathalie

doi:10.1186/s12964-020-00693-9

Cited by 18 publications

(15 citation statements)

References 160 publications

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“…Among the differentially phosphorylated protein phosphatases, we observed an overrepresentation of phosphopeptides mapping to non-receptor protein tyrosine phosphatase subfamily (or PTPNs). Several PTPNs have been previously implicated in cytokine signaling [ 54 ]. For example, PTPN2 was found to regulate IFNgamma-induced cytokine signaling in THP1 monocytes through decreased STAT1 and STAT3 activity and the secretion of IL-6 and MCP-1 [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Temporal Quantitative Phosphoproteomics Profiling of Interleukin-33 Signaling Network Reveals Unique Modulators of Monocyte Activation

Rex

Subbannayya

Modi

et al. 2022

Cells

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Interleukin-33 (IL-33), a member of the IL-1 superfamily cytokines, is an endogenous danger signal and a nuclear-associated cytokine. It is one of the essential mediators of both innate and adaptive immune responses. Aberrant IL-33 signaling has been demonstrated to play a defensive role against various infectious and inflammatory diseases. Although the signaling responses mediated by IL-33 have been previously reported, the temporal signaling dynamics are yet to be explored. To this end, we applied quantitative temporal phosphoproteomics analysis to elucidate pathways and proteins induced by IL-33 in THP-1 monocytes. Employing a TMT labeling-based quantitation and titanium dioxide (TiO2)-based phosphopeptide enrichment strategy followed by mass spectrometry analysis, we identified and quantified 9448 unique phosphopeptides corresponding to 3392 proteins that showed differential regulation. Of these, 171 protein kinases, 60 phosphatases and 178 transcription factors were regulated at different phases of IL-33 signaling. In addition to the confirmed activation of canonical signaling modules including MAPK, NFκB, PI3K/AKT modules, pathway analysis of the time-dependent phosphorylation dynamics revealed enrichment of several cellular processes, including leukocyte adhesion, response to reactive oxygen species, cell cycle checkpoints, DNA damage and repair pathways. The detailed quantitative phosphoproteomic map of IL-33 signaling will serve as a potentially useful resource to study its function in the context of inflammatory and pathological conditions.

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Section: Discussionmentioning

confidence: 99%

Temporal Quantitative Phosphoproteomics Profiling of Interleukin-33 Signaling Network Reveals Unique Modulators of Monocyte Activation

Rex

Subbannayya

Modi

et al. 2022

Cells

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“…This occurs upon binding to PIP 2 before its interaction with TLRs (12). Subsequent interaction with TLRs' TIR domain is facilitated by tyrosine phosphorylation of selected TLRs and their adaptor molecules by several tyrosine kinases, including Bruton's tyrosine kinase (BTK), Src, Lyn, Syk, etc (43,44). For example, 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).…”

Section: Tirap and Bruton's Tyrosine Kinase (Btk)mentioning

confidence: 99%

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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“…Another possible factor affecting the TLR signaling is intracellular zinc levels ( 36 , 37 ). In TLR-induced downstream pathways, signal transduction largely depends on posttranslational modifications of proteins including phosphorylation, dephosphorylation and ubiquitination ( 57 – 59 ). The activity of protein kinases ( 60 ), and phosphatases ( 61 – 63 ) is influenced by zinc levels.…”

Section: Regulators Of Tlr Signaling In Hnecsmentioning

confidence: 99%

TLR Signals in Epithelial Cells in the Nasal Cavity and Paranasal Sinuses

et al. 2021

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The respiratory tract is constantly at risk of invasion by microorganisms such as bacteria, viruses, and fungi. In particular, the mucosal epithelium of the nasal cavity and paranasal sinuses is at the very forefront of the battles between the host and the invading pathogens. Recent studies have revealed that the epithelium not only constitutes a physical barrier but also takes an essential role in the activation of the immune system. One of the mechanisms equipped in the epithelium to fight against microorganisms is the Toll-like receptor (TLR) response. TLRs recognize common structural components of microorganisms and activate the innate immune system, resulting in the production of a plethora of cytokines and chemokines in the response against microbes. As the epithelia-derived cytokines are deeply involved in the pathogenesis of inflammatory conditions in the nasal cavity and paranasal sinuses, such as chronic rhinosinusitis (CRS) and allergic rhinitis (AR), the molecules involved in the TLR response may be utilized as therapeutic targets for these diseases. There are several differences in the TLR response between nasal and bronchial epithelial cells, and knowledge of the TLR signals in the upper airway is sparse compared to that in the lower airway. In this review, we provide recent evidence on TLR signaling in the upper airway, focusing on the expression, regulation, and responsiveness of TLRs in human nasal epithelial cells (HNECs). We also discuss how TLRs in the epithelium are involved in the pathogenesis of, and possible therapeutic targeting, for CRS and AR.

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Phosphatases in toll-like receptors signaling: the unfairly-forgotten

Cited by 18 publications

References 160 publications

Temporal Quantitative Phosphoproteomics Profiling of Interleukin-33 Signaling Network Reveals Unique Modulators of Monocyte Activation

Temporal Quantitative Phosphoproteomics Profiling of Interleukin-33 Signaling Network Reveals Unique Modulators of Monocyte Activation

TIRAP in the Mechanism of Inflammation

TLR Signals in Epithelial Cells in the Nasal Cavity and Paranasal Sinuses

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