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Autophagy Aug 2023Copper is an essential trace element in biological systems, maintaining the activity of enzymes and the function of transcription factors. However, at high... (Review)
Review
Copper is an essential trace element in biological systems, maintaining the activity of enzymes and the function of transcription factors. However, at high concentrations, copper ions show increased toxicity by inducing regulated cell death, such as apoptosis, paraptosis, pyroptosis, ferroptosis, and cuproptosis. Furthermore, copper ions can trigger macroautophagy/autophagy, a lysosome-dependent degradation pathway that plays a dual role in regulating the survival or death fate of cells under various stress conditions. Pathologically, impaired copper metabolism due to environmental or genetic causes is implicated in a variety of human diseases, such as rare Wilson disease and common cancers. Therapeutically, copper-based compounds are potential chemotherapeutic agents that can be used alone or in combination with other drugs or approaches to treat cancer. Here, we review the progress made in understanding copper metabolic processes and their impact on the regulation of cell death and autophagy. This knowledge may help in the design of future clinical tools to improve cancer diagnosis and treatment. ACSL4, acyl-CoA synthetase long chain family member 4; AIFM1/AIF, apoptosis inducing factor mitochondria associated 1; AIFM2, apoptosis inducing factor mitochondria associated 2; ALDH, aldehyde dehydrogenase; ALOX, arachidonate lipoxygenase; AMPK, AMP-activated protein kinase; APAF1, apoptotic peptidase activating factor 1; ATF4, activating transcription factor 4; ATG, autophagy related; ATG13, autophagy related 13; ATG5, autophagy related 5; ATOX1, antioxidant 1 copper chaperone; ATP, adenosine triphosphate; ATP7A, ATPase copper transporting alpha; ATP7B, ATPase copper transporting beta; BAK1, BCL2 antagonist/killer 1; BAX, BCL2 associated X apoptosis regulator; BBC3/PUMA, BCL2 binding component 3; BCS, bathocuproinedisulfonic acid; BECN1, beclin 1; BID, BH3 interacting domain death agonist; BRCA1, BRCA1 DNA repair associated; BSO, buthionine sulphoximine; CASP1, caspase 1; CASP3, caspase 3; CASP4/CASP11, caspase 4; CASP5, caspase 5; CASP8, caspase 8; CASP9, caspase 9; CCS, copper chaperone for superoxide dismutase; CD274/PD-L1, CD274 molecule; CDH2, cadherin 2; CDKN1A/p21, cyclin dependent kinase inhibitor 1A; CDKN1B/p27, cyclin-dependent kinase inhibitor 1B; COMMD10, COMM domain containing 10; CoQ10, coenzyme Q 10; CoQ10H2, reduced coenzyme Q 10; COX11, cytochrome c oxidase copper chaperone COX11; COX17, cytochrome c oxidase copper chaperone COX17; CP, ceruloplasmin; CYCS, cytochrome c, somatic; DBH, dopamine beta-hydroxylase; DDIT3/CHOP, DNA damage inducible transcript 3; DLAT, dihydrolipoamide S-acetyltransferase; DTC, diethyldithiocarbamate; EIF2A, eukaryotic translation initiation factor 2A; EIF2AK3/PERK, eukaryotic translation initiation factor 2 alpha kinase 3; ER, endoplasmic reticulum; ESCRT-III, endosomal sorting complex required for transport-III; ETC, electron transport chain; FABP3, fatty acid binding protein 3; FABP7, fatty acid binding protein 7; FADD, Fas associated via death domain; FAS, Fas cell surface death receptor; FASL, Fas ligand; FDX1, ferredoxin 1; GNAQ/11, G protein subunit alpha q/11; GPX4, glutathione peroxidase 4; GSDMD, gasdermin D; GSH, glutathione; HDAC, histone deacetylase; HIF1, hypoxia inducible factor 1; HIF1A, hypoxia inducible factor 1 subunit alpha; HMGB1, high mobility group box 1; IL1B, interleukin 1 beta; IL17, interleukin 17; KRAS, KRAS proto-oncogene, GTPase; LOX, lysyl oxidase; LPCAT3, lysophosphatidylcholine acyltransferase 3; MAP1LC3, microtubule associated protein 1 light chain 3; MAP2K1, mitogen-activated protein kinase kinase 1; MAP2K2, mitogen-activated protein kinase kinase 2; MAPK, mitogen-activated protein kinases; MAPK14/p38, mitogen-activated protein kinase 14; MEMO1, mediator of cell motility 1; MT-CO1/COX1, mitochondrially encoded cytochrome c oxidase I; MT-CO2/COX2, mitochondrially encoded cytochrome c oxidase II; MTOR, mechanistic target of rapamycin kinase; MTs, metallothioneins; NAC, N-acetylcysteine; NFKB/NF-Κb, nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3; NPLOC4/NPL4, NPL4 homolog ubiquitin recognition factor; PDE3B, phosphodiesterase 3B; PDK1, phosphoinositide dependent protein kinase 1; PHD, prolyl-4-hydroxylase domain; PIK3C3/VPS34, phosphatidylinositol 3-kinase catalytic subunit type 3; PMAIP1/NOXA, phorbol-12-myristate-13-acetate-induced protein 1; POR, cytochrome P450 oxidoreductase; PUFA-PL, PUFA of phospholipids; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; SCO1, synthesis of cytochrome C oxidase 1; SCO2, synthesis of cytochrome C oxidase 2; SLC7A11, solute carrier family 7 member 11; SLC11A2/DMT1, solute carrier family 11 member 2; SLC31A1/CTR1, solute carrier family 31 member 1; SLC47A1, solute carrier family 47 member 1; SOD1, superoxide dismutase; SP1, Sp1 transcription factor; SQSTM1/p62, sequestosome 1; STEAP4, STEAP4 metalloreductase; TAX1BP1, Tax1 binding protein 1; TEPA, tetraethylenepentamine; TFEB, transcription factor EB; TM, tetrathiomolybdate; TP53/p53, tumor protein p53; TXNRD1, thioredoxin reductase 1; UCHL5, ubiquitin C-terminal hydrolase L5; ULK1, Unc-51 like autophagy activating kinase 1; ULK1, unc-51 like autophagy activating kinase 1; ULK2, unc-51 like autophagy activating kinase 2; USP14, ubiquitin specific peptidase 14; VEGF, vascular endothelial gro wth factor; XIAP, X-linked inhibitor of apoptosis.
Topics: Humans; Autophagy; Tumor Suppressor Protein p53; Apoptosis Inducing Factor; Copper; Ubiquinone; Electron Transport Complex IV; Autophagy-Related Protein-1 Homolog; Proto-Oncogene Proteins p21(ras); Apoptosis; Caspases; Hypoxia-Inducible Factor 1; Superoxide Dismutase; Neoplasms; Ions; Proto-Oncogene Proteins c-bcl-2
PubMed: 37055935
DOI: 10.1080/15548627.2023.2200554 -
Nature Jan 2024Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options. No new antibiotic chemical class with activity...
Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options. No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years. Here we report the identification and optimization of tethered macrocyclic peptide (MCP) antibiotics with potent antibacterial activity against CRAB. The mechanism of action of this molecule class involves blocking the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane, through inhibition of the LptBFGC complex. A clinical candidate derived from the MCP class, zosurabalpin (RG6006), effectively treats highly drug-resistant contemporary isolates of CRAB both in vitro and in mouse models of infection, overcoming existing antibiotic resistance mechanisms. This chemical class represents a promising treatment paradigm for patients with invasive infections due to CRAB, for whom current treatment options are inadequate, and additionally identifies LptBFGC as a tractable target for antimicrobial drug development.
Topics: Animals; Humans; Mice; Acinetobacter baumannii; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Lipopolysaccharides; Microbial Sensitivity Tests; Membrane Transport Proteins; Biological Transport; Disease Models, Animal; Acinetobacter Infections; Drug Development
PubMed: 38172634
DOI: 10.1038/s41586-023-06873-0 -
Channels (Austin, Tex.) Dec 2024Voltage-gated sodium (Na) channels govern membrane excitability by initiating and propagating action potentials. Consistent with their physiological significance,... (Review)
Review
Voltage-gated sodium (Na) channels govern membrane excitability by initiating and propagating action potentials. Consistent with their physiological significance, dysfunction, or mutations in these channels are associated with various channelopathies. Na channels are thereby major targets for various clinical and investigational drugs. In addition, a large number of natural toxins, both small molecules and peptides, can bind to Na channels and modulate their functions. Technological breakthrough in cryo-electron microscopy (cryo-EM) has enabled the determination of high-resolution structures of eukaryotic and eventually human Na channels, alone or in complex with auxiliary subunits, toxins, and drugs. These studies have not only advanced our comprehension of channel architecture and working mechanisms but also afforded unprecedented clarity to the molecular basis for the binding and mechanism of action (MOA) of prototypical drugs and toxins. In this review, we will provide an overview of the recent advances in structural pharmacology of Na channels, encompassing the structural map for ligand binding on Na channels. These findings have established a vital groundwork for future drug development.
Topics: Humans; Voltage-Gated Sodium Channels; Cryoelectron Microscopy; Action Potentials; Peptides; Sodium
PubMed: 38033122
DOI: 10.1080/19336950.2023.2287832 -
Cell Jan 2024During development, morphogens pattern tissues by instructing cell fate across long distances. Directly visualizing morphogen transport in situ has been inaccessible, so...
During development, morphogens pattern tissues by instructing cell fate across long distances. Directly visualizing morphogen transport in situ has been inaccessible, so the molecular mechanisms ensuring successful morphogen delivery remain unclear. To tackle this longstanding problem, we developed a mouse model for compromised sonic hedgehog (SHH) morphogen delivery and discovered that endocytic recycling promotes SHH loading into signaling filopodia called cytonemes. We optimized methods to preserve in vivo cytonemes for advanced microscopy and show endogenous SHH localized to cytonemes in developing mouse neural tubes. Depletion of SHH from neural tube cytonemes alters neuronal cell fates and compromises neurodevelopment. Mutation of the filopodial motor myosin 10 (MYO10) reduces cytoneme length and density, which corrupts neuronal signaling activity of both SHH and WNT. Combined, these results demonstrate that cytoneme-based signal transport provides essential contributions to morphogen dispersion during mammalian tissue development and suggest MYO10 is a key regulator of cytoneme function.
Topics: Animals; Mice; Biological Transport; Cell Membrane Structures; Hedgehog Proteins; Myosins; Pseudopodia; Signal Transduction; Neural Tube
PubMed: 38171360
DOI: 10.1016/j.cell.2023.12.003 -
The Journal of Clinical Investigation Nov 2023The facilitative GLUT1 and GLUT3 hexose transporters are expressed abundantly in macrophages, but whether they have distinct functions remains unclear. We confirmed that...
The facilitative GLUT1 and GLUT3 hexose transporters are expressed abundantly in macrophages, but whether they have distinct functions remains unclear. We confirmed that GLUT1 expression increased after M1 polarization stimuli and found that GLUT3 expression increased after M2 stimulation in macrophages. Conditional deletion of Glut3 (LysM-Cre Glut3fl/fl) impaired M2 polarization of bone marrow-derived macrophages. Alternatively activated macrophages from the skin of patients with atopic dermatitis showed increased GLUT3 expression, and a calcipotriol-induced model of atopic dermatitis was rescued in LysM-Cre Glut3fl/fl mice. M2-like macrophages expressed GLUT3 in human wound tissues as assessed by transcriptomics and costaining, and GLUT3 expression was significantly decreased in nonhealing, compared with healing, diabetic foot ulcers. In an excisional wound healing model, LysM-Cre Glut3fl/fl mice showed significantly impaired M2 macrophage polarization and delayed wound healing. GLUT3 promoted IL-4/STAT6 signaling, independently of its glucose transport activity. Unlike plasma membrane-localized GLUT1, GLUT3 was localized primarily to endosomes and was required for the efficient endocytosis of IL-4Rα subunits. GLUT3 interacted directly with GTP-bound RAS in vitro and in vivo through its intracytoplasmic loop domain, and this interaction was required for efficient STAT6 activation and M2 polarization. PAK activation and macropinocytosis were also impaired without GLUT3, suggesting broader roles for GLUT3 in the regulation of endocytosis. Thus, GLUT3 is required for efficient alternative macrophage polarization and function, through a glucose transport-independent, RAS-mediated role in the regulation of endocytosis and IL-4/STAT6 activation.
Topics: Animals; Humans; Mice; Dermatitis, Atopic; Endocytosis; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 3; Interleukin-4; Macrophage Activation; Macrophages; Wound Healing
PubMed: 37721853
DOI: 10.1172/JCI170706 -
Basic Research in Cardiology Aug 2023Activation of signal transducer and activator of transcription 3 (STAT3) has been identified as a key cardioprotective signal not only in animal studies but also in... (Review)
Review
Activation of signal transducer and activator of transcription 3 (STAT3) has been identified as a key cardioprotective signal not only in animal studies but also in humans-in animals, STAT3 is causally involved in cardioprotection. In response to late ischemic conditioning, canonical function of STAT3 activation upregulates the expression of cardioprotective and anti-apoptotic proteins. In its non-canonical function, STAT3 is activated during ischemic conditioning and is part of the cardioprotective cytosolic survival activating factor enhancement pathway. Activated STAT3 is imported and localized to the mitochondria. Mitochondrial STAT3 stimulates the activity of mitochondrial electron transport chain complex I, reduces mitochondrial reactive oxygen species production and mitochondrial permeability transition pore opening. Finally, two novel aspects of STAT activation in cardioprotection are discussed: a genetic variance of the STAT encoding region as a potential primordial confounding variable for cardioprotection, and the cardioprotective potential of sodium-glucose cotransporter 2 inhibitors through STAT3 activation.
Topics: Animals; Humans; STAT3 Transcription Factor; Mitochondria; Mitochondrial Permeability Transition Pore; Reactive Oxygen Species
PubMed: 37620559
DOI: 10.1007/s00395-023-01003-3 -
Annual Review of Nutrition Aug 2023Amino acids derived from protein digestion are important nutrients for the growth and maintenance of organisms. Approximately half of the 20 proteinogenic amino acids... (Review)
Review
Amino acids derived from protein digestion are important nutrients for the growth and maintenance of organisms. Approximately half of the 20 proteinogenic amino acids can be synthesized by mammalian organisms, while the other half are essential and must be acquired from the nutrition. Absorption of amino acids is mediated by a set of amino acid transporters together with transport of di- and tripeptides. They provide amino acids for systemic needs and for enterocyte metabolism. Absorption is largely complete at the end of the small intestine. The large intestine mediates the uptake of amino acids derived from bacterial metabolism and endogenous sources. Lack of amino acid transporters and peptide transporter delays the absorption of amino acids and changes sensing and usage of amino acids by the intestine. This can affect metabolic health through amino acid restriction, sensing of amino acids, and production of antimicrobial peptides.
Topics: Humans; Animals; Biological Transport; Intestines; Amino Acids; Nutritional Status; Enterocytes; Antifibrinolytic Agents; Mammals
PubMed: 37285555
DOI: 10.1146/annurev-nutr-061121-094344 -
Nature Communications Sep 2023The BCL-2 inhibitor Venetoclax is a promising agent for the treatment of acute myeloid leukemia (AML). However, many patients are refractory to Venetoclax, and...
The BCL-2 inhibitor Venetoclax is a promising agent for the treatment of acute myeloid leukemia (AML). However, many patients are refractory to Venetoclax, and resistance develops quickly. ATP-binding cassette (ABC) transporters mediate chemotherapy resistance but their role in modulating the activity of targeted small-molecule inhibitors is unclear. Using CRISPR/Cas9 screening, we find that loss of ABCC1 strongly increases the sensitivity of AML cells to Venetoclax. Genetic and pharmacologic ABCC1 inactivation potentiates the anti-leukemic effects of BCL-2 inhibitors and efficiently re-sensitizes Venetoclax-resistant leukemia cells. Conversely, ABCC1 overexpression induces resistance to BCL-2 inhibitors by reducing intracellular drug levels, and high ABCC1 levels predicts poor response to Venetoclax therapy in patients. Consistent with ABCC1-specific export of glutathionylated substrates, inhibition of glutathione metabolism increases the potency of BCL-2 inhibitors. These results identify ABCC1 and glutathione metabolism as mechanisms limiting efficacy of BCL-2 inhibitors, which may pave the way to development of more effective therapies.
Topics: Humans; Sulfonamides; ATP-Binding Cassette Transporters; Antineoplastic Agents; Leukemia, Myeloid, Acute; Glutathione; Proto-Oncogene Proteins c-bcl-2
PubMed: 37726279
DOI: 10.1038/s41467-023-41229-2 -
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 -
Frontiers in Immunology 2023T-helper 22 (Th22) cells represent a novel subset of CD4 T cells that exhibit distinctive characteristics, namely the secretion of IL-22 while abstaining from secreting... (Review)
Review
T-helper 22 (Th22) cells represent a novel subset of CD4 T cells that exhibit distinctive characteristics, namely the secretion of IL-22 while abstaining from secreting IL-17 and interferon-γ (IFN-γ). These cells serve as the primary source of IL-22, and both Th22 cells and IL-22 are believed to play a role in maintaining intestinal mucosal homeostasis in inflammatory bowel disease (IBD). However, the precise functions of Th22 cells and IL-22 in this context remain a subject of debate. In this work, we aimed to elucidate their impact on the integrity of the intestinal mucosal barrier by presenting an overview of the molecular structure characteristics and functional effects of Th22 cells and IL-22. Furthermore, we would explore targeted treatment approaches and potential therapeutic strategies focusing on the Th22 and IL-22 pathways.
Topics: Humans; T-Lymphocytes, Helper-Inducer; Biological Transport; Homeostasis; Inflammatory Bowel Diseases; Interferon-gamma
PubMed: 37646028
DOI: 10.3389/fimmu.2023.1221068