The toll like receptor 7 pathway and the sex bias of systemic lupus erythematosus

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Фев. 20, 2025

Systemic lupus erythematosus (SLE) predominately affects women with a ratio of females-to-males about 9:1. The complement sex chromosomes may play and important role in the mechanism bias. Previous work has shown that men Klinefleter's syndrome (47,XXY) as well 47,XXX are found excess among SLE patients Sjogren's disease, systemic sclerosis idiopathic inflammatory myositis. cells more than one X chromosome, all but is inactivated. However, chromosome inactivation, mediated by long noncoding RNA X-inactive specific transcript, or XIST, not complete approximately 10% genes non-recombining region escaping inactivation. In TLR7 signaling pathway, both TLR adaptor interacting endolysosomal SLC15A4 (TASL) escape Comparing male female immune cells, there increased related to expression these chromosome. Cells also express while do not. source ligand for TLR7, been increase signaling. Thus, we propose mechanisms operating act mutual way mediate an dose effect bias autoimmune disease.

Язык: Английский

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The multiple roles of interferon regulatory factor family in health and disease

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Окт. 9, 2024

Interferon Regulatory Factors (IRFs), a family of transcription factors, profoundly influence the immune system, impacting both physiological and pathological processes. This review explores diverse functions nine mammalian IRF members, each featuring conserved domains essential for interactions with other factors cofactors. These allow IRFs to modulate broad spectrum processes, encompassing host defense, response, cell development. Conversely, their pivotal role in regulation implicates them pathophysiology various diseases, such as infectious autoimmune disorders, metabolic cancers. In this context, display dichotomous nature, functioning tumor suppressors promoters, contingent upon specific disease milieu. Post-translational modifications IRFs, including phosphorylation ubiquitination, play crucial modulating function, stability, activation. As prospective biomarkers therapeutic targets, present promising opportunities intervention. Further research is needed elucidate precise mechanisms governing regulation, potentially pioneering innovative strategies, particularly cancer treatment, where equilibrium activities paramount importance.

Язык: Английский

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The TLR7/9 adaptors TASL and TASL2 mediate IRF5-dependent antiviral responses and autoimmunity in mouse

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 24, 2025

Abstract Endosomal nucleic acid sensing by Toll-like receptors (TLRs) is central to antimicrobial immunity and several autoimmune conditions such as systemic lupus erythematosus (SLE). The innate immune adaptor TASL mediates, via the interaction with SLC15A4, activation of IRF5 downstream human TLR7, TLR8 TLR9, but pathophysiological functions this axis remain unexplored. Here we show that SLC15A4 deficiency results in a selective block TLR7/9-induced activation, while loss leads strong incomplete impairment, which depends on cell type TLR engaged. This residual activity ascribed previously uncharacterized paralogue, Gm6377 , named here TASL2. Double knockout TASL2 (TASL DKO ) phenocopies SLC15A4-deficient feeble mice showing comparable impairment humoral responses. Consequently, fail control chronic LCMV infection, being protected pristane-induced SLE disease model. Our study thus demonstrates critical role TASL/TASL2 for TLR7/9-driven inflammatory responses, further supporting therapeutic potential targeting complex related diseases.

Язык: Английский

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Lysosomal Ion Channels and Transporters: Recent Findings, Therapeutic Potential, and Technical Approaches

Bioelectricity, Год журнала: 2025, Номер 7(1), С. 29 - 57

Опубликована: Март 1, 2025

In recent years, there has been a growing interest in lysosomal ion channels and transporters due to their critical role maintaining function involvement variety of diseases, particularly storage cancer, neurodegenerative disorders. Recent advancements research techniques, including manual automated patch clamp (APC) electrophysiology, solid-supported membrane-based electrophysiology (SSME), fluorescence-based imaging, have further enhanced our ability investigate both physiological pathological conditions, spurring drug discovery efforts. Several pharmaceutical companies are now developing therapies aimed at modulating these improve disease. Small molecules targeting like transient receptor potential mucolipin (TRPML) 1 TMEM175, as well drugs pH, currently preclinical clinical development. This review provides an overview the health disease, highlights cutting-edge techniques used study them, discusses therapeutic treatment various diseases. Furthermore, addition summarizing discoveries, we contribute novel functional data on cystinosin, TRPML1, two-pore channel 2 (TPC2), utilizing SSME APC approaches.

Язык: Английский

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A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Окт. 20, 2023

Dysregulation of pathogen-recognition pathways the innate immune system is associated with multiple autoimmune disorders. Due to intricacies molecular network involved, identification pathway- and disease-specific therapeutics has been challenging. Using a phenotypic assay monitoring degradation adapter TASL, we identify feeblin, chemical entity which inhibits nucleic acid-sensing TLR7/8 pathway activating IRF5 by disrupting SLC15A4-TASL module. A high-resolution cryo-EM structure feeblin SLC15A4 reveals that inhibitor binds lysosomal outward-open conformation incompatible TASL binding on cytoplasmic side, leading TASL. This mechanism action exploits conformational switch converts target-binding event into proteostatic regulation effector protein interrupting TLR7/8-IRF5 signaling preventing downstream proinflammatory responses. Considering all components involved have genetically systemic lupus erythematosus blocks responses in disease-relevant human cells from patients, study represents proof-of-concept for development against this disease.

Язык: Английский

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MDSC-derived S100A8/9 contributes to lupus pathogenesis by promoting TLR7-mediated activation of macrophages and dendritic cells

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Март 1, 2024

Abstract Toll-like receptors (TLRs), especially TLR7, play an important role in systemic lupus erythematosus (SLE) pathogenesis. However, the regulatory mechanism underlying abnormal activation of TLR pathways patients with SLE has not been elucidated. Notably, accumulating evidence indicates that myeloid-derived suppressor cells (MDSCs) are regulators inflammation and autoimmune diseases. Compared healthy control subjects, have a greater proportion MDSCs among peripheral blood mononuclear (PBMCs); however, effect on TLR7 pathway determined. In present study, significantly promoted macrophages dendritic (DCs), exacerbating imiquimod-induced model. RNA-sequencing analysis revealed significant overexpression S100 calcium-binding protein A8 (S100A8) S100A9 from diseased MRL/ lpr mice. vitro vivo studies demonstrated S100A8/9 effectively deficiency reversed promoting lupus. Mechanistically, MDSC-derived upregulated interferon gamma (IFN-γ) secretion by IFN-γ subsequently autocrine manner. Taken together, these findings suggest promote pathogenesis through S100A8/9-IFN-γ axis. Our study identified target for therapy.

Язык: Английский

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Nucleic acid triggers of autoimmunity and autoinflammation

Current Opinion in Immunology, Год журнала: 2025, Номер 93, С. 102535 - 102535

Опубликована: Янв. 30, 2025

Язык: Английский

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ARIES domains: functional signaling units of type I interferon responses

FEBS Journal, Год журнала: 2025, Номер unknown

Опубликована: Фев. 18, 2025

The innate immune system relies on a network of signaling proteins classified by shared domains, which serve as functional units that orchestrate inflammatory and host defensive activities. Within type I interferon (IFN) responses, the stimulator genes protein (STING), mitochondrial antiviral‐signaling (MAVS), Toll‐IL‐1 receptor‐resistance domain‐containing adapter‐inducing interferon‐β (TRIF), Toll‐like receptor adapter interacting with SLC15A4 lysosome (TASL), insulin tyrosine kinase substrate 53 kDa (IRSp53), GEM (GMIP) utilize conserved pLxIS motif to recruit IRF family transcription factors. Notably, functions within larger unit, is referred here an Activator Interferon Expression via (ARIES) domain. ARIES domains consist adjacent activation motifs together drive IFN responses. This review explores how promote responses distinct mechanisms, localization, regulation metabolic shifts, underscoring their evolutionary conservation critical role in defense.

Язык: Английский

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Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Окт. 20, 2023

Toll-like receptors (TLRs) are a class of proteins that play critical roles in recognizing pathogens and initiating innate immune responses. TASL, recently identified adaptor protein for endolysosomal TLR7/8/9 signaling, is recruited by the lysosomal proton-coupled amino-acid transporter SLC15A4, then activates IRF5, which turn triggers transcription type I interferons cytokines. Here, we report three cryo-electron microscopy (cryo-EM) structures human SLC15A4 apo monomeric dimeric state as TASL-bound complex. The forms an outward-facing conformation, with form showing extensive interface involving four cholesterol molecules. structure complex reveals unprecedented interaction mode solute carriers. During recruitment undergoes conformational change from outward-facing, lumen-exposed to inward-facing binding pocket, allowing N-terminal helix TASL be inserted into. Our findings provide insights into molecular basis regulatory switch carrier offers important framework structure-guided drug discovery targeting SLC15A4-TASL-related autoimmune diseases.

Язык: Английский

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The IRAK1/IRF5 axis initiates IL-12 response by dendritic cells and control of Toxoplasma gondii infection

Cell Reports, Год журнала: 2024, Номер 43(2), С. 113795 - 113795

Опубликована: Фев. 1, 2024

Activation of endosomal Toll-like receptor (TLR) 7, TLR9, and TLR11/12 is a key event in the resistance against parasite Toxoplasma gondii. Endosomal TLR engagement leads to expression interleukin (IL)-12 via myddosome, protein complex containing MyD88 IL-1 receptor-associated kinase (IRAK) 4 addition IRAK1 or IRAK2. In murine macrophages, IRAK2 essential for IL-12 production TLRs but, surprisingly, Irak2

Язык: Английский

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