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Cell Apr 2024Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion...
Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of CD8 T cells. Tumor cells outcompete CD8 T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction, thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8 T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8 T cells and increases the efficacy of cancer therapies.
Topics: Taurine; CD8-Positive T-Lymphocytes; Animals; Humans; Mice; Cell Line, Tumor; Mice, Inbred C57BL; Endoplasmic Reticulum Stress; Activating Transcription Factor 4; Signal Transduction; Female; Membrane Transport Proteins; STAT3 Transcription Factor; Membrane Glycoproteins
PubMed: 38565142
DOI: 10.1016/j.cell.2024.03.011 -
Trends in Biochemical Sciences Sep 2023Solute carrier (SLCs) transporters mediate the transport of a broad range of solutes across biological membranes. Dysregulation of SLCs has been associated with various... (Review)
Review
Solute carrier (SLCs) transporters mediate the transport of a broad range of solutes across biological membranes. Dysregulation of SLCs has been associated with various pathologies, including metabolic and neurological disorders, as well as cancer and rare diseases. SLCs are therefore emerging as key targets for therapeutic intervention with several recently approved drugs targeting these proteins. Unlocking this large and complex group of proteins is essential to identifying unknown SLC targets and developing next-generation SLC therapeutics. Recent progress in experimental and computational techniques has significantly advanced SLC research, including drug discovery. Here, we review emerging topics in therapeutic discovery of SLCs, focusing on state-of-the-art approaches in structural, chemical, and computational biology, and discuss current challenges in transporter drug discovery.
Topics: Humans; Solute Carrier Proteins; Membrane Transport Proteins; Biological Transport; Drug Discovery; Neoplasms
PubMed: 37355450
DOI: 10.1016/j.tibs.2023.05.011 -
Science (New York, N.Y.) Nov 2023Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol...
Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake, but how cholesterol moves downstream of NPC1L1 is unknown. We show that Aster-B and Aster-C are critical for nonvesicular cholesterol movement in enterocytes. Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate PM cholesterol and show endoplasmic reticulum cholesterol depletion. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, the Aster pathway can be targeted with a small-molecule inhibitor to manipulate cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.
Topics: Animals; Mice; Biological Transport; Cholesterol, Dietary; Intestinal Absorption; Membrane Transport Proteins; Mice, Inbred C57BL; Enterocytes; Liver X Receptors; Humans; Jejunum; Mice, Knockout
PubMed: 37943936
DOI: 10.1126/science.adf0966 -
Nature Communications Oct 2023Niemann-Pick C1-like 1 (NPC1L1) is essential for intestinal cholesterol absorption. Together with the cholesterol-rich and Flotillin-positive membrane microdomain,...
Niemann-Pick C1-like 1 (NPC1L1) is essential for intestinal cholesterol absorption. Together with the cholesterol-rich and Flotillin-positive membrane microdomain, NPC1L1 is internalized via clathrin-mediated endocytosis and transported to endocytic recycling compartment (ERC). When ERC cholesterol level decreases, NPC1L1 interacts with LIMA1 and moves back to plasma membrane. However, how cholesterol leaves ERC is unknown. Here, we find that, in male mice, intracellular bile acids facilitate cholesterol transport to other organelles, such as endoplasmic reticulum, in a non-micellar fashion. When cholesterol level in ERC is decreased by bile acids, the NPC1L1 carboxyl terminus that previously interacts with the cholesterol-rich membranes via the ALAL residues dissociates from membrane, exposing the QKR motif for LIMA1 recruitment. Then NPC1L1 moves back to plasma membrane. This study demonstrates an intracellular cholesterol transport function of bile acids and explains how the substantial amount of cholesterol in NPC1L1-positive compartments is unloaded in enterocytes during cholesterol absorption.
Topics: Animals; Male; Mice; Biological Transport; Cell Membrane; Cholesterol; Intestinal Absorption; Membrane Transport Proteins
PubMed: 37833289
DOI: 10.1038/s41467-023-42179-5 -
Nature Aug 2023To replicate inside macrophages and cause tuberculosis, Mycobacterium tuberculosis must scavenge a variety of nutrients from the host. The mammalian cell entry (MCE)...
To replicate inside macrophages and cause tuberculosis, Mycobacterium tuberculosis must scavenge a variety of nutrients from the host. The mammalian cell entry (MCE) proteins are important virulence factors in M. tuberculosis, where they are encoded by large gene clusters and have been implicated in the transport of fatty acids and cholesterol across the impermeable mycobacterial cell envelope. Very little is known about how cargos are transported across this barrier, and it remains unclear how the approximately ten proteins encoded by a mycobacterial mce gene cluster assemble to transport cargo across the cell envelope. Here we report the cryo-electron microscopy (cryo-EM) structure of the endogenous Mce1 lipid-import machine of Mycobacterium smegmatis-a non-pathogenic relative of M. tuberculosis. The structure reveals how the proteins of the Mce1 system assemble to form an elongated ABC transporter complex that is long enough to span the cell envelope. The Mce1 complex is dominated by a curved, needle-like domain that appears to be unrelated to previously described protein structures, and creates a protected hydrophobic pathway for lipid transport across the periplasm. Our structural data revealed the presence of a subunit of the Mce1 complex, which we identified using a combination of cryo-EM and AlphaFold2, and name LucB. Our data lead to a structural model for Mce1-mediated lipid import across the mycobacterial cell envelope.
Topics: Animals; Bacterial Proteins; Cryoelectron Microscopy; Lipids; Membrane Transport Proteins; Mycobacterium tuberculosis; Tuberculosis; Virus Internalization; Virulence Factors; ATP-Binding Cassette Transporters; Periplasm; Protein Domains; Hydrophobic and Hydrophilic Interactions; Multiprotein Complexes
PubMed: 37495693
DOI: 10.1038/s41586-023-06366-0 -
Cell Death and Differentiation Aug 2023The mitochondrial permeability transition (mPT) describes a Ca-dependent and cyclophilin D (CypD)-facilitated increase of inner mitochondrial membrane permeability that... (Review)
Review
The mitochondrial permeability transition (mPT) describes a Ca-dependent and cyclophilin D (CypD)-facilitated increase of inner mitochondrial membrane permeability that allows diffusion of molecules up to 1.5 kDa in size. It is mediated by a non-selective channel, the mitochondrial permeability transition pore (mPTP). Sustained mPTP opening causes mitochondrial swelling, which ruptures the outer mitochondrial membrane leading to subsequent apoptotic and necrotic cell death, and is implicated in a range of pathologies. However, transient mPTP opening at various sub-conductance states may contribute several physiological roles such as alterations in mitochondrial bioenergetics and rapid Ca efflux. Since its discovery decades ago, intensive efforts have been made to identify the exact pore-forming structure of the mPT. Both the adenine nucleotide translocase (ANT) and, more recently, the mitochondrial FF (F)-ATP synthase dimers, monomers or c-subunit ring alone have been implicated. Here we share the insights of several key investigators with different perspectives who have pioneered mPT research. We critically assess proposed models for the molecular identity of the mPTP and the mechanisms underlying its opposing roles in the life and death of cells. We provide in-depth insights into current controversies, seeking to achieve a degree of consensus that will stimulate future innovative research into the nature and role of the mPTP.
Topics: Mitochondrial Permeability Transition Pore; Mitochondrial Membrane Transport Proteins; Consensus; Mitochondria; Mitochondrial Membranes
PubMed: 37460667
DOI: 10.1038/s41418-023-01187-0 -
Nature Communications Oct 2023Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoimmune disorders. Due to the intricacies of the molecular...
Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoimmune disorders. Due to the intricacies of the molecular network involved, the identification of pathway- and disease-specific therapeutics has been challenging. Using a phenotypic assay monitoring the degradation of the immune adapter TASL, we identify feeblin, a chemical entity which inhibits the nucleic acid-sensing TLR7/8 pathway activating IRF5 by disrupting the SLC15A4-TASL adapter module. A high-resolution cryo-EM structure of feeblin with SLC15A4 reveals that the inhibitor binds a lysosomal outward-open conformation incompatible with TASL binding on the cytoplasmic side, leading to degradation of TASL. This mechanism of action exploits a conformational switch and converts a target-binding event into proteostatic regulation of the effector protein TASL, interrupting the TLR7/8-IRF5 signaling pathway and preventing downstream proinflammatory responses. Considering that all components involved have been genetically associated with systemic lupus erythematosus and that feeblin blocks responses in disease-relevant human immune cells from patients, the study represents a proof-of-concept for the development of therapeutics against this disease.
Topics: Humans; Toll-Like Receptor 7; Interferon Regulatory Factors; Lupus Erythematosus, Systemic; Signal Transduction; Anti-Inflammatory Agents; Nerve Tissue Proteins; Membrane Transport Proteins
PubMed: 37863876
DOI: 10.1038/s41467-023-42070-3 -
Journal of Cell Science Jul 2023Protein translocases, such as the bacterial SecY complex, the Sec61 complex of the endoplasmic reticulum (ER) and the mitochondrial translocases, facilitate the...
Protein translocases, such as the bacterial SecY complex, the Sec61 complex of the endoplasmic reticulum (ER) and the mitochondrial translocases, facilitate the transport of proteins across membranes. In addition, they catalyze the insertion of integral membrane proteins into the lipid bilayer. Several membrane insertases cooperate with these translocases, thereby promoting the topogenesis, folding and assembly of membrane proteins. Oxa1 and BamA family members serve as core components in the two major classes of membrane insertases. They facilitate the integration of proteins with α-helical transmembrane domains and of β-barrel proteins into lipid bilayers, respectively. Members of the Oxa1 family were initially found in the internal membranes of bacteria, mitochondria and chloroplasts. Recent studies, however, also identified several Oxa1-type insertases in the ER, where they serve as catalytically active core subunits in the ER membrane protein complex (EMC), the guided entry of tail-anchored (GET) and the GET- and EMC-like (GEL) complex. The outer membrane of bacteria, mitochondria and chloroplasts contain β-barrel proteins, which are inserted by members of the BamA family. In this Cell Science at a Glance article and the accompanying poster, we provide an overview of these different types of membrane insertases and discuss their function.
Topics: Membrane Transport Proteins; Membrane Proteins; Mitochondria; Membranes; Bacteria; Bacterial Outer Membrane Proteins; Escherichia coli Proteins
PubMed: 37417332
DOI: 10.1242/jcs.261219 -
Nature Metabolism Aug 2023Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by...
Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin's suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.
Topics: Humans; Mice; Animals; Adipose Tissue, Brown; Serotonin; Sertraline; Serotonin Plasma Membrane Transport Proteins; Obesity; Thermogenesis; Metabolic Diseases
PubMed: 37537371
DOI: 10.1038/s42255-023-00839-2 -
International Journal of Molecular... Aug 2023Proper brain development essentially depends on the timed availability of sufficient amounts of thyroid hormone (TH). This, in turn, necessitates a tightly regulated... (Review)
Review
Proper brain development essentially depends on the timed availability of sufficient amounts of thyroid hormone (TH). This, in turn, necessitates a tightly regulated expression of TH signaling components such as TH transporters, deiodinases, and TH receptors in a brain region- and cell-specific manner from early developmental stages onwards. Abnormal TH levels during critical stages, as well as mutations in TH signaling components that alter the global and/or local thyroidal state, result in detrimental consequences for brain development and neurological functions that involve alterations in central neurotransmitter systems. Thus, the question as to how TH signaling is implicated in the development and maturation of different neurotransmitter and neuromodulator systems has gained increasing attention. In this review, we first summarize the current knowledge on the regulation of TH signaling components during brain development. We then present recent advances in our understanding on how altered TH signaling compromises the development of cortical glutamatergic neurons, inhibitory GABAergic interneurons, cholinergic and dopaminergic neurons. Thereby, we highlight novel mechanistic insights and point out open questions in this evolving research field.
Topics: Thyroid Hormones; Receptors, Thyroid Hormone; Thyroid Gland; Brain; Membrane Transport Proteins
PubMed: 37569727
DOI: 10.3390/ijms241512352