Molecular basis of TASL recruitment by the peptide/histidine transporter 1, PHT1

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

Опубликована: Сен. 14, 2023

PHT1 is a histidine /oligopeptide transporter with an essential role in Toll-like receptor innate immune responses. It can act as by recruiting the adaptor protein TASL which leads to type I interferon production via IRF5. Persistent stimulation of this signalling pathway known be involved pathogenesis systemic lupus erythematosus (SLE). Understanding how recruits at molecular level, therefore clinically important for development therapeutics against SLE and other autoimmune diseases. Here we present Cryo-EM structure stabilized outward-open conformation. By combining biochemical structural modeling techniques propose model PHT1-TASL complex, first 16 N-terminal residues fold into helical that bind central cavity inward-open conformation PHT1. This work provides critical insights basis PHT1/TASL mediated production.

Язык: Английский

---

A high-resolution view of the immune and stromal cell response to Haemophilus ducreyi infection in human volunteers

mBio, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

ABSTRACT Haemophilus ducreyi causes the genital ulcer disease chancroid and cutaneous ulcers in children. To study its pathogenesis, we developed a human challenge model which infect skin on upper arm of volunteers with H. to pustular stage disease. The has been used define lesional architecture, describe immune infiltrate into infected sites using flow cytometry, explore molecular basis response bulk RNA-seq. Here, single cell RNA-seq (scRNA-seq) spatial transcriptomics simultaneously characterize multiple types within determine cellular origin differentially expressed transcripts that had previously identified by We obtained paired biopsies pustules wounded (mock infected) from five for scRNA-seq. 13 major types, including T- NK-like cells, macrophages, dendritic as well other typically found skin. Immune were enriched pustules, some subtypes exclusive pustules. Sufficient tissue specimens available four volunteers. cells highly associated antigen presentation types. In type I interferon stimulation was high areas presentation—especially macrophages near abscess—compared wounds. Together, our data provide high-resolution view infection pathogen. IMPORTANCE A due an extracellular bacterial pathogen not yet defined. identify level are present who fail spontaneously clear form immune-activated stromal compared sites. Pustules formed despite expression pro-inflammatory cytokines, such IL-1β interferon. Interferon most evident proximal abscess. pustule may be tempered regulatory T express indoleamine 2,3-dioxygenase, leading failure system .

Язык: Английский

---

Solute carrier family 15 member 4, an emerging therapeutic target for systemic lupus erythematosus

International Reviews of Immunology, Год журнала: 2025, Номер unknown, С. 1 - 15

Опубликована: Апрель 21, 2025

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by excessive production of type I interferons (IFNs) and autoantibodies with limited effective clinical treatments. Solute carrier family 15 member 4 (SLC15A4), proton-coupled oligopeptide transporter, facilitates the transmembrane transport L-histidine some di- tripeptides from lysosome to cytosol. A growing body evidence has elucidated critical role SLC15A4 in pathogenesis progression SLE. Genome-wide association studies have identified as new susceptibility locus Further mechanistical demonstrated that involves IFNs plasmacytoid dendritic cells (pDCs) its necessity B for autoantibody models. These strongly support potential promising therapeutic target This review aims summarize recent advances understanding SLE development SLC15A4-targeted inhibitors well discuss treatment.

Язык: Английский

---

The role of age-associated B cells in systemic lupus erythematosus

Journal of Autoimmunity, Год журнала: 2025, Номер 154, С. 103433 - 103433

Опубликована: Май 6, 2025

Язык: Английский

---

Metabolic control from the endolysosome: lysosome-resident amino acid transporters open novel therapeutic possibilities

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Сен. 15, 2023

Amino acid transporters are generally recognized as machinery that transport amino acids from the extracellular environment into cytoplasm. Although their primary function is uptake of to supply cell with nutrients and energy, endolysosome-resident (EL-aa) possess several unique functions in accordance localization intracellular vesicular membranes. They play pivotal roles maintenance metabolic homeostasis via direct involvement sensing pathway, which regulates activity mechanistic target rapamycin complex 1 (mTORC1), a master regulator cellular metabolism. Additionally, some EL-aa contribute dynamic endolysosomes, including regulation endolysosomal acidity, by carrying out endolysosomes. In addition, act scaffold gather signaling molecules multiple enzymes control metabolism on membrane. Among transporters, solute carrier family 15 member 4 (SLC15A4) preferentially expressed immune cells, macrophages, dendritic B plays key role integration inflammatory signals. this review, we summarize our recent findings transporter contributions endolysosomes cells focusing SLC15 family, SLC15A4 SLC15A3, discuss uniqueness universality. We also potential targeting these for development novel therapeutic strategies diseases. Because highly significantly alter them would provide great advantage ensuring wide safety margin.

Язык: Английский

---

New approaches to the control of chronic inflammatory diseases with a focus on the endolysosomal system of immune cells

International Immunology, Год журнала: 2024, Номер 37(1), С. 15 - 24

Опубликована: Июль 1, 2024

Chronic inflammation is implicated in many types of diseases, including cardiovascular, neurodegenerative, metabolic, and immune disorders. The search for therapeutic targets to control chronic often involves narrowing down the various molecules associated with pathology that have been discovered by omics analyses. Herein, a different approach identify against proposed one such target discussed as an example. In chronically inflamed tissues, large number cells receive diverse proinflammatory signals, intracellular signals are intricately integrated, complicated intercellular interactions orchestrated. This review focuses on effectively blocking this chaotic inflammatory signaling network via endolysosomal system, which acts cellular hub. endolysosomes, mediated pathogen sensors, Toll-like receptors, from nutrient metabolic pathways integrally regulated. Disruption endolysosome results strong anti-inflammatory effect disrupting pathways, sensor-mediated multiple cells. endolysosome-resident amino acid transporter, solute carrier family 15 member 4 (SLC15A4), plays important role regulation endolysosome-mediated promising several autoimmune diseases. mechanisms SLC15A4 regulates responses may provide proof concept efficacy strategies targeting cell endolysosomes.

Язык: Английский

---

UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling

Nature Immunology, Год журнала: 2024, Номер 25(12), С. 2234 - 2246

Опубликована: Ноя. 20, 2024

Язык: Английский

---

CCDC134 controls TLR biogenesis through the ER chaperone Gp96

The Journal of Experimental Medicine, Год журнала: 2024, Номер 222(3)

Опубликована: Дек. 10, 2024

Toll-like receptors (TLRs) are central to initiate immune responses against invading pathogens. To ensure host defense while avoiding aberrant activation leading pathogenic inflammation and autoimmune diseases, TLRs tightly controlled by multilevel regulatory mechanisms. Through a loss-of-function genetic screen in reporter cell line engineered undergo death upon TLR7-induced IRF5 activation, we identified here CCDC134 as an essential factor for TLR responses. deficiency impaired endolysosomal TLR-induced NF-κB, MAPK, well downstream production of proinflammatory cytokines type I interferons. We further demonstrated that is endoplasmic reticulum (ER)-resident interactor Gp96 (HSP90B1/Grp94), ER chaperone folding trafficking plasma membrane TLRs. stability its loss led hyperglycosylation ER-associated protein degradation (ERAD)-mediated clearance. Accordingly, the folding, maturation, TLRs, resulting blunted inflammatory stimulation. Altogether, this study reveals regulator Gp96, thereby controlling biogenesis

Язык: Английский

---

MAVS: The Next STING in Cancers and Other Diseases

Critical Reviews in Oncology/Hematology, Год журнала: 2024, Номер unknown, С. 104610 - 104610

Опубликована: Дек. 1, 2024

Язык: Английский

---

Muropeptides and muropeptide transporters impact on host immune response

Gut Microbes, Год журнала: 2024, Номер 16(1)

Опубликована: Окт. 22, 2024

In bacteria, the cell envelope is key element surrounding and protecting bacterial content from mechanical or osmotic damages. It allows selective interchanges of solutes, ions, cellular debris, drugs between compartments external environment, thanks to presence transmembrane proteins called transporters. The major component peptidoglycan, consisting long linear glycan strands cross-linked by short peptide stems. During growth under stress conditions, peptidoglycan fragments, muropeptides, are released bacteria recognized host Pattern Recognition Receptor, promoting activation their innate defense mechanisms. review sums up salient aspects microbiota-host interaction with a focus on NOD-dependent immune response accountability muropeptide transporters in crosstalk antibiotic resistance. Furthermore, it retraces discoveries applications microorganisms-derived components such as vaccines vaccine adjuvants.

Язык: Английский

---