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Nature Immunology Jan 2024Intestinal intraepithelial lymphocytes (IELs) exhibit prompt innate-like responses to microenvironmental cues and require strict control of effector functions. Here we...
Intestinal intraepithelial lymphocytes (IELs) exhibit prompt innate-like responses to microenvironmental cues and require strict control of effector functions. Here we showed that Aiolos, an Ikaros zinc-finger family member encoded by Ikzf3, acted as a regulator of IEL activation. Ikzf3 CD8αα IELs had elevated expression of NK receptors, cytotoxic enzymes, cytokines and chemokines. Single-cell RNA sequencing of Ikzf3 and Ikzf3 IELs showed an amplified effector machinery in Ikzf3 CD8αα IELs compared to Ikzf3 counterparts. Ikzf3 CD8αα IELs had increased responsiveness to interleukin-15, which explained a substantial part, but not all, of the observed phenotypes. Aiolos binding sites were close to those for the transcription factors STAT5 and RUNX, which promote interleukin-15 signaling and cytolytic programs, and Ikzf3 deficiency partially increased chromatin accessibility and histone acetylation in these regions. Ikzf3 deficiency in mice enhanced susceptibility to colitis, underscoring the relevance of Aiolos in regulating the effector function in IELs.
Topics: Animals; Mice; CD8 Antigens; Interleukin-15; Intestinal Mucosa; Intraepithelial Lymphocytes; Mice, Inbred C57BL; Mice, Knockout; Transcription Factors
PubMed: 38049581
DOI: 10.1038/s41590-023-01693-w -
Basic & Clinical Pharmacology &... Nov 2023LAT1 and 4F2hc form a heterodimeric membrane protein complex, which functions as one of the best characterized amino acid transporters. Since LAT1-4F2hc is required for... (Review)
Review
LAT1 and 4F2hc form a heterodimeric membrane protein complex, which functions as one of the best characterized amino acid transporters. Since LAT1-4F2hc is required for the efficient uptake of essential amino acids and hormones, it promotes cellular growth, in part, by stimulating mTORC1 (mechanistic target of rapamycin complex 1) signalling and by repressing the integrated stress response (ISR). Gain or loss of LAT1-4F2hc function is associated with cancer, diabetes, and immunological and neurological diseases. Hence, LAT1-4F2hc represents an attractive drug target for disease treatment. Specific targeting of LAT1-4F2hc will be facilitated by the increasingly detailed understanding of its molecular architecture, which provides important concepts for its function and regulation. Here, we summarize (i) structural insights that help to explain how LAT1 and 4F2hc assemble to transport amino acids across membranes, (ii) the role of LAT1-4F2hc in key metabolic signalling pathways, and (iii) how derailing these processes could contribute to diseases.
Topics: Humans; Amino Acid Transport Systems; Amino Acids; Biological Transport; Fusion Regulatory Protein 1, Heavy Chain; Large Neutral Amino Acid-Transporter 1; Mechanistic Target of Rapamycin Complex 1
PubMed: 36460306
DOI: 10.1111/bcpt.13821 -
JACC. Basic To Translational Science Sep 2023Mitochondrial dysfunction is suggested to be a major contributor for the progression of heart failure (HF). Here we examined the role of syntaxin 17 (STX17) in the...
Mitochondrial dysfunction is suggested to be a major contributor for the progression of heart failure (HF). Here we examined the role of syntaxin 17 (STX17) in the progression of HF. Cardiac-specific knockout manifested cardiac dysfunction and mitochondrial damage, associated with reduced levels of p(S616)-dynamin-related protein 1 (DRP1) in mitochondria-associated endoplasmic reticulum membranes and dampened mitophagy. Cardiac STX17 overexpression promoted DRP1-dependent mitophagy and attenuated transverse aortic constriction-induced contractile and mitochondrial damage. Furthermore, STX17 recruited cyclin-dependent kinase-1 through its SNARE domain onto mitochondria-associated endoplasmic reticulum membranes, to phosphorylate DRP1 at Ser616 and promote DRP1-mediated mitophagy upon transverse aortic constriction stress. These findings indicate the potential therapeutic benefit of targeting STX17 in the mitigation of HF.
PubMed: 37791317
DOI: 10.1016/j.jacbts.2023.04.006 -
Current Cardiology Reports Oct 2023We aim to give a concise overview of the different clinical manifestations of both acute and long-term radiotherapy-related pericardial diseases, the underlying... (Review)
Review
PURPOSE OF REVIEW
We aim to give a concise overview of the different clinical manifestations of both acute and long-term radiotherapy-related pericardial diseases, the underlying pathophysiology as well as the diagnosis and treatment options.
RECENT FINDINGS
Radiotherapy-related pericardial disease is common, but despite radiotherapy being a cornerstone of many cancer treatments, this disease entity is relatively underrepresented in clinical trials, resulting in a paucity of research data on pathophysiology and management. Since the development of innovative cancer treatments, survival has significantly improved. Therefore, the importance of long-term treatment-related side effects increases, most notably cancer treatment-related cardiovascular toxicity. In patients undergoing radiotherapy as a part of their cancer treatment, radiotherapy-related pericardial disease can manifest early (during or shortly after radiotherapy administration) or very late (several years to decades after treatment). This exceptionally long latency period confronts physicians with treatment-related side effects of radiotherapy regimens that may have been abandoned already.
Topics: Humans; Heart Diseases; Radiation Injuries; Pericardium
PubMed: 37584875
DOI: 10.1007/s11886-023-01933-3 -
International Journal of Molecular... Nov 2023Membrane-spanning portions of proteins' polypeptide chains are commonly known as their transmembrane domains (TMDs). The structural organisation and dynamic behaviour of... (Review)
Review
Membrane-spanning portions of proteins' polypeptide chains are commonly known as their transmembrane domains (TMDs). The structural organisation and dynamic behaviour of TMDs from proteins of various families, be that receptors, ion channels, enzymes etc., have been under scrutiny on the part of the scientific community for the last few decades. The reason for such attention is that, apart from their obvious role as an "anchor" in ensuring the correct orientation of the protein's extra-membrane domains (in most cases functionally important), TMDs often actively and directly contribute to the operation of "the protein machine". They are capable of transmitting signals across the membrane, interacting with adjacent TMDs and membrane-proximal domains, as well as with various ligands, etc. Structural data on TMD arrangement are still fragmentary at best due to their complex molecular organisation as, most commonly, dynamic oligomers, as well as due to the challenges related to experimental studies thereof. Inter alia, this is especially true for viral fusion proteins, which have been the focus of numerous studies for quite some time, but have provoked unprecedented interest in view of the SARS-CoV-2 pandemic. However, despite numerous structure-centred studies of the spike (S) protein effectuating target cell entry in coronaviruses, structural data on the TMD as part of the entire spike protein are still incomplete, whereas this segment is known to be crucial to the spike's fusogenic activity. Therefore, in attempting to bring together currently available data on the structure and dynamics of spike proteins' TMDs, the present review aims to tackle a highly pertinent task and contribute to a better understanding of the molecular mechanisms underlying virus-mediated fusion, also offering a rationale for the design of novel efficacious methods for the treatment of infectious diseases caused by SARS-CoV-2 and related viruses.
Topics: Humans; Membrane Fusion; Protein Domains; Viral Fusion Proteins; Peptides; SARS-CoV-2
PubMed: 38003610
DOI: 10.3390/ijms242216421 -
Membranes Jan 2024Direct air capture (DAC) is an emerging negative CO emission technology that aims to introduce a feasible method for CO capture from the atmosphere. Unlike carbon... (Review)
Review
Direct air capture (DAC) is an emerging negative CO emission technology that aims to introduce a feasible method for CO capture from the atmosphere. Unlike carbon capture from point sources, which deals with flue gas at high CO concentrations, carbon capture directly from the atmosphere has proved difficult due to the low CO concentration in ambient air. Current DAC technologies mainly consider sorbent-based systems; however, membrane technology can be considered a promising DAC approach since it provides several advantages, e.g., lower energy and operational costs, less environmental footprint, and more potential for small-scale ubiquitous installations. Several recent advancements in validating the feasibility of highly permeable gas separation membrane fabrication and system design show that membrane-based direct air capture (m-DAC) could be a complementary approach to sorbent-based DAC, e.g., as part of a hybrid system design that incorporates other DAC technologies (e.g., solvent or sorbent-based DAC). In this article, the ongoing research and DAC application attempts via membrane separation have been reviewed. The reported membrane materials that could potentially be used for m-DAC are summarized. In addition, the future direction of m-DAC development is discussed, which could provide perspective and encourage new researchers' further work in the field of m-DAC.
PubMed: 38392657
DOI: 10.3390/membranes14020030 -
Nature Microbiology May 2024Children infected with SARS-CoV-2 rarely progress to respiratory failure. However, the risk of mortality in infected people over 85 years of age remains high. Here we...
Children infected with SARS-CoV-2 rarely progress to respiratory failure. However, the risk of mortality in infected people over 85 years of age remains high. Here we investigate differences in the cellular landscape and function of paediatric (<12 years), adult (30-50 years) and older adult (>70 years) ex vivo cultured nasal epithelial cells in response to infection with SARS-CoV-2. We show that cell tropism of SARS-CoV-2, and expression of ACE2 and TMPRSS2 in nasal epithelial cell subtypes, differ between age groups. While ciliated cells are viral replication centres across all age groups, a distinct goblet inflammatory subtype emerges in infected paediatric cultures and shows high expression of interferon-stimulated genes and incomplete viral replication. In contrast, older adult cultures infected with SARS-CoV-2 show a proportional increase in basaloid-like cells, which facilitate viral spread and are associated with altered epithelial repair pathways. We confirm age-specific induction of these cell types by integrating data from in vivo COVID-19 studies and validate that our in vitro model recapitulates early epithelial responses to SARS-CoV-2 infection.
Topics: Humans; COVID-19; SARS-CoV-2; Angiotensin-Converting Enzyme 2; Adult; Middle Aged; Aged; Epithelial Cells; Serine Endopeptidases; Nasal Mucosa; Child; Age Factors; Virus Replication; Child, Preschool; Viral Tropism; Male; Female; Aged, 80 and over; Cells, Cultured; Adolescent; Infant
PubMed: 38622380
DOI: 10.1038/s41564-024-01658-1 -
Antioxidants & Redox Signaling Oct 2023Mitochondrial (mt) reticulum network in the cell possesses amazing ultramorphology of parallel lamellar cristae, formed by the invaginated inner mitochondrial membrane.... (Review)
Review
Mitochondrial (mt) reticulum network in the cell possesses amazing ultramorphology of parallel lamellar cristae, formed by the invaginated inner mitochondrial membrane. Its non-invaginated part, the inner boundary membrane (IBM) forms a cylindrical sandwich with the outer mitochondrial membrane (OMM). Crista membranes (CMs) meet IBM at crista junctions (CJs) of mt cristae organizing system (MICOS) complexes connected to OMM sorting and assembly machinery (SAM). Cristae dimensions, shape, and CJs have characteristic patterns for different metabolic regimes, physiological and pathological situations. Cristae-shaping proteins were characterized, namely rows of ATP-synthase dimers forming the crista lamella edges, MICOS subunits, optic atrophy 1 (OPA1) isoforms and mitochondrial genome maintenance 1 (MGM1) filaments, prohibitins, and others. Detailed cristae ultramorphology changes were imaged by focused-ion beam/scanning electron microscopy. Dynamics of crista lamellae and mobile CJs were demonstrated by nanoscopy in living cells. With tBID-induced apoptosis a single entirely fused cristae reticulum was observed in a mitochondrial spheroid. The mobility and composition of MICOS, OPA1, and ATP-synthase dimeric rows regulated by post-translational modifications might be exclusively responsible for cristae morphology changes, but ion fluxes across CM and resulting osmotic forces might be also involved. Inevitably, cristae ultramorphology should reflect also mitochondrial redox homeostasis, but details are unknown. Disordered cristae typically reflect higher superoxide formation. To link redox homeostasis to cristae ultramorphology and define markers, recent progress will help in uncovering mechanisms involved in proton-coupled electron transfer the respiratory chain and in regulation of cristae architecture, leading to structural determination of superoxide formation sites and cristae ultramorphology changes in diseases. 39, 635-683.
Topics: Mitochondrial Membranes; Superoxides; Homeostasis; Oxidation-Reduction; Adenosine Triphosphate; Mitochondrial Proteins
PubMed: 36793196
DOI: 10.1089/ars.2022.0173 -
Experimental and computational approaches for membrane protein insertion and topology determination.Methods (San Diego, Calif.) Jun 2024Membrane proteins play pivotal roles in a wide array of cellular processes and constitute approximately a quarter of the protein-coding genes across all organisms.... (Review)
Review
Membrane proteins play pivotal roles in a wide array of cellular processes and constitute approximately a quarter of the protein-coding genes across all organisms. Despite their ubiquity and biological significance, our understanding of these proteins remains notably less comprehensive compared to their soluble counterparts. This disparity in knowledge can be attributed, in part, to the inherent challenges associated with employing specialized techniques for the investigation of membrane protein insertion and topology. This review will center on a discussion of molecular biology methodologies and computational prediction tools designed to elucidate the insertion and topology of helical membrane proteins.
Topics: Membrane Proteins; Computational Biology; Humans; Models, Molecular
PubMed: 38604415
DOI: 10.1016/j.ymeth.2024.03.012