-
Hepatology (Baltimore, Md.) Oct 2023HCC is a malignant disease. Compared with tyrosine kinase inhibitors (the classical therapy), immune checkpoint inhibitors are more effective in the treatment of HCC,...
BACKGROUND AND AIMS
HCC is a malignant disease. Compared with tyrosine kinase inhibitors (the classical therapy), immune checkpoint inhibitors are more effective in the treatment of HCC, despite their limited efficacy. Among these restricted factors, exhaustion of tumor-infiltrated lymphocytes, especially CD8 + T cells, is a core event. We aimed to determine the key factors contributing to CD8 + T-cell infiltration in HCC and investigate the underlying mechanisms.
APPROACH AND RESULTS
Using machine learning and multiplex immunohistochemistry analysis, we showed that dedicator of cytokinesis protein 2 (DOCK2) was a potential indicator of infiltrated CD8 + T cells in HCC. Using RNA sequencing, flow cytometry analysis, and mouse HCC models, we demonstrated that DOCK2 inactivation accounted for infiltrated CD8 + T-cell exhaustion in tumors. Using quasi-targeted metabolomics, mass spectrum, and mass cytometry by time of flight analysis, we found that cholesterol sulfate synthesized by sulfotransferase 2B1 in tumor cells suppressed DOCK2 enzymatic activity of T cells. Through virtual screening, molecular docking simulation, and experiments validation, we demonstrated that tolazamide reversed DOCK2 inactivation-mediated CD8 + T-cell exhaustion and enhanced anti-programmed death-ligand 1 antibody+apatinib immunotherapeutic effects on HCC.
CONCLUSIONS
This study indicates that DOCK2 controls CD8 + T-cell infiltration in HCC, and cholesterol sulfate synthesized by sulfotransferase 2B1 in tumor cells promotes effector T-cell exhaustion. The findings suggest that the usage of conventional drugs affects immunotherapy efficacy in HCC patients.
Topics: Mice; Animals; Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Molecular Docking Simulation; T-Cell Exhaustion; CD8-Positive T-Lymphocytes; Sulfotransferases; Tumor Microenvironment; Guanine Nucleotide Exchange Factors; GTPase-Activating Proteins
PubMed: 36626623
DOI: 10.1097/HEP.0000000000000025 -
Nature Chemical Biology Jul 2023Tyrosine sulfation is a common posttranslational modification in mammals. To date, it has been thought to be limited to secreted and transmembrane proteins, but little...
Tyrosine sulfation is a common posttranslational modification in mammals. To date, it has been thought to be limited to secreted and transmembrane proteins, but little is known about tyrosine sulfation on nuclear proteins. Here we report that SULT1B1 is a histone sulfotransferase that can sulfate the tyrosine 99 residue of nascent histone H3 in cytosol. The sulfated histone H3 can be transported into the nucleus and majorly deposited in the promoter regions of genes in chromatin. While the H3Y99 residue is buried inside octameric nucleosome, dynamically regulated subnucleosomal structures provide chromatin-H3Y99sulf the opportunity of being recognized and bound by PRMT1, which deposits H4R3me2a in chromatin. Disruption of H3Y99sulf reduces PRMT1 binding to chromatin, H4R3me2a level and gene transcription. These findings reveal the mechanisms underlying H3Y99 sulfation and its cross-talk with H4R3me2a to regulate gene transcription. This study extends the spectrum of tyrosine sulfation on nuclear proteins and the repertoire of histone modifications regulating chromatin functions.
Topics: Animals; Histones; Tyrosine; Chromatin; Nuclear Proteins; Transcription, Genetic; Mammals
PubMed: 36805701
DOI: 10.1038/s41589-023-01267-9 -
Nature Chemical Biology Oct 2023
Topics: Sulfotransferases; Sulfates
PubMed: 37749348
DOI: 10.1038/s41589-023-01438-8 -
Science Immunology Jan 2024Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize bacterial riboflavin-based metabolites as activating antigens. Although MAIT cells are...
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize bacterial riboflavin-based metabolites as activating antigens. Although MAIT cells are found in tissues, it is unknown whether any host tissue-derived antigens exist. Here, we report that a sulfated bile acid, cholic acid 7-sulfate (CA7S), binds the nonclassical MHC class I protein MR1 and is recognized by MAIT cells. CA7S is a host-derived metabolite whose levels were reduced by more than 98% in germ-free mice. Deletion of the sulfotransferase 2a family of enzymes () responsible for CA7S synthesis reduced the number of thymic MAIT cells in mice. Moreover, recognition of CA7S induced MAIT cell survival and the expression of a homeostatic gene signature. By contrast, recognition of a previously described foreign antigen, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), drove MAIT cell proliferation and the expression of inflammatory genes. Thus, CA7S is an endogenous antigen for MAIT cells, which promotes their development and function.
Topics: Animals; Mice; Mucosal-Associated Invariant T Cells; Bile Acids and Salts; Ligands; Sulfates; Minor Histocompatibility Antigens; Antigens
PubMed: 38277465
DOI: 10.1126/sciimmunol.ade6924 -
Gastroenterology Jul 2023Pancreatitis is a disease continuum, starting with acute pancreatitis (AP) and progressing in some cases to recurrent acute pancreatitis (RAP) and chronic pancreatitis...
Distinct Serum Immune Profiles Define the Spectrum of Acute and Chronic Pancreatitis From the Multicenter Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) Study.
BACKGROUND & AIMS
Pancreatitis is a disease continuum, starting with acute pancreatitis (AP) and progressing in some cases to recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). Currently, there are no approved therapies or early diagnostic or prognostic biomarkers for pancreatitis. The current study examined whether patient serum immune profiling could identify noninvasive biomarkers and provide mechanistic insight into the disease continuum of pancreatitis.
METHODS
Using Olink immunoassay, we assessed the protein levels of 92 immune markers in serum samples from participants enrolled in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) study of the Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) consortium. Samples (N = 231) were obtained from individuals without pancreatic disease (n = 56) and from those with chronic abdominal pain (CAP) (n = 24), AP (n = 38), RAP (n = 56), and CP (n = 57).
RESULTS
A total of 33 immune markers differentiated the combined pancreatitis groups from controls. Immune markers related to interleukin (IL) 17 signaling distinguished CP from AP and RAP. Similarly, the serum level of IL17A and C-C motif chemokine ligand 20 differentiated CP from CAP, suggesting the involvement of T helper 17 cells in CP pathogenesis. The receiver operator characteristic curve with 2 immune markers (IL17A and sulfotransferase 1A1) could differentiate CP from CAP (optimistic area under the curve = 0.78). The macrophage classical activation pathway elevated along the continuum of pancreatitis, suggesting an accumulation of proinflammatory signals over disease progression. Several immune markers were associated with smoking, alcohol, and diabetes status.
CONCLUSIONS
Immune profiling of serum samples from a large pancreatitis cohort led to identifying distinct immune markers that could serve as potential biomarkers to differentiate the varying pancreatitis disease states. In addition, the finding of IL17 signaling in CP could provide insight into the immune mechanisms underlying disease progression.
Topics: Humans; Acute Disease; Pancreatitis, Chronic; Disease Progression; Abdominal Pain; Diabetes Mellitus; Biomarkers
PubMed: 37061168
DOI: 10.1053/j.gastro.2023.03.236 -
Antioxidants & Redox Signaling Nov 2023Persulfides/polysulfides are sulfur-catenated molecular species (, R-S-R', > 2; R-S-H, > 1, with R = cysteine, glutathione, and proteins), such as... (Review)
Review
Persulfides/polysulfides are sulfur-catenated molecular species (, R-S-R', > 2; R-S-H, > 1, with R = cysteine, glutathione, and proteins), such as cysteine persulfide (CysSSH). These species are abundantly formed as endogenous metabolites in mammalian and human cells and tissues. However, the persulfide synthesis mechanism has yet to be thoroughly discussed. We used β-(4-hydroxyphenyl)ethyl iodoacetamide and mass spectrometry to develop sulfur metabolomics, a highly precise, quantitative analytical method for sulfur metabolites. With this method, we detected appreciable amounts of different persulfide species in biological specimens from various organisms, from the domains Bacteria, Archaea, and Eukarya. By using our rigorously quantitative approach, we identified cysteinyl-tRNA synthetase (CARS) as a novel persulfide synthase, and we found that the CysSSH synthase activity of CARS is highly conserved from the domains Bacteria to Eukarya. Because persulfide synthesis is found not only with CARS but also with other sulfotransferase enzymes in many organisms, persulfides/polysulfides are expected to contribute as fundamental elements to substantially diverse biological phenomena. In fact, persulfide generation in higher organisms-that is, plants and animals-demonstrated various physiological functions that are mediated by redox signaling, such as regulation of energy metabolism, infection, inflammation, and cell death, including ferroptosis. Investigating CARS-dependent persulfide production may clarify various pathways of redox signaling in physiological and pathophysiological conditions and may thereby promote the development of preventive and therapeutic measures for oxidative stress as well as different inflammatory, metabolic, and neurodegenerative diseases. 39, 983-999.
Topics: Animals; Humans; Sulfides; Oxidation-Reduction; Cysteine; Sulfur; Mammals
PubMed: 37565274
DOI: 10.1089/ars.2023.0405 -
Physiological Research Dec 2023While there are hundreds of synthetic steroids conjugates with acids, sugars, proteins and other molecules, only two types of conjugates occur in living organisms,... (Review)
Review
While there are hundreds of synthetic steroids conjugates with acids, sugars, proteins and other molecules, only two types of conjugates occur in living organisms, namely sulfates and glucuronides. Steroid glucuronidation in the human liver is the main mechanism controlling the levels and biological activity of unconjugated hormones, and glucuronides are their main excretion products. This process is generally irreversible. On the other hand, sulfates possess their own biological activity that differs from that of the unconjugated steroid, emphasizing the importance of steroid sulfatases and sulfotransferases. Due to their negative charge, steroid sulfates cannot cross the blood-cell barrier and have to use transporters. Their efflux is mediated by specific transporters of the ATP binding cassette protein group, which thus are further factors controlling their physiological effects. Steroid sulfates, especially dehydroepiandrosterone sulfate (DHEAS) are neuroactive steroids, with well-known effects as allosteric modulators of some neurotransmitter receptors, functioning as ion channels, such as gamma-aminobutyric acid, type A (GABAA) receptors or N-methyl-D-aspartate (NMDA) receptors. In this minireview, we highlight some recent findings of non-genomic steroid sulfate actions through specific G-protein coupled receptors (GPCR), which we believe show the way of further research. A few studies have even indicated that sulfates such as DHEAS may even indirectly regulate gene expression via ligand binding to the membrane receptor and, through G-protein and second messenger formation, activate proteins like cAMP Regulated Elements Binding protein (CREB), which then binds to regulated DNA elements of the expressed gene, in a "classical" genomic effect.
Topics: Humans; Sulfates; Phosphorylation; Signal Transduction; Biological Transport; Steroids
PubMed: 38116768
DOI: 10.33549/physiolres.935080 -
Acute Medicine & Surgery 2023The endothelial glycocalyx covers the lumen of blood vessels throughout the body and plays an important role in endothelial homeostasis. Advances in electron microscopy... (Review)
Review
The endothelial glycocalyx covers the lumen of blood vessels throughout the body and plays an important role in endothelial homeostasis. Advances in electron microscopy techniques have provided clues to better understand the structure and composition of identical vascular endothelial glycocalyx. The morphology and thickness of the endothelial glycocalyx differ from organ to organ. The content of the endothelial glycocalyx covering the vascular lumen differs even in the brain, heart, and lungs, which have the same continuous capillaries. Various types of inflammation are known to attenuate the endothelial glycocalyx; however, we found that the morphology of the glycocalyx damaged by acute inflammation differed from that damaged by chronic inflammation. Acute inflammation breaks the endothelial glycocalyx unevenly, whereas chronic inflammation leads to the overall shortening of the endothelial glycocalyx. The same drug has different effects on the endothelial glycocalyx, depending on the location of the target blood vessels. This difference in response may reflect not only the size and shape of the endothelial glycocalyx but also the different constituents. In the cardiac tissue, the expression of glypican-1, a core protein of the endothelial glycocalyx, was enhanced. By contrast, in the pulmonary tissue, the expression of heparan sulfate 6-O-sulfotransferase 1 and endothelial cell-specific molecule-1 significantly increased in the treatment group compared with that in the no-treatment group. In this review, we present the latest findings on the evolution of the vascular endothelial glycocalyx and consider the microstructural differences.
PubMed: 37808968
DOI: 10.1002/ams2.896 -
Frontiers in Plant Science 2023Phytosulfokines (PSKs) are a class of disulfated pentapeptides and are regarded as plant peptide hormones. PSK-α, -γ, -δ, and -ϵ are four bioactive PSKs that are... (Review)
Review
Phytosulfokines (PSKs) are a class of disulfated pentapeptides and are regarded as plant peptide hormones. PSK-α, -γ, -δ, and -ϵ are four bioactive PSKs that are reported to have roles in plant growth, development, and immunity. In this review, we summarize recent advances in PSK biosynthesis, signaling, and function. PSKs are encoded by precursor genes that are widespread in higher plants. PSKs maturation from these precursors requires a sulfation step, which is catalyzed by a tyrosylprotein sulfotransferase, as well as proteolytic cleavage by subtilisin serine proteases. PSK signaling is mediated by plasma membrane-localized receptors PSKRs that belong to the leucine-rich repeat receptor-like kinase family. Moreover, multiple biological functions can be attributed to PSKs, including promoting cell division and cell growth, regulating plant reproduction, inducing somatic embryogenesis, enhancing legume nodulation, and regulating plant resistance to biotic and abiotic stress. Finally, we propose several research directions in this field. This review provides important insights into PSKs that will facilitate biotechnological development and PSK application in agriculture.
PubMed: 38250441
DOI: 10.3389/fpls.2023.1326964 -
Steroids Jan 2024Sulfation and desulfation of steroids are opposing processes that regulate the activation, metabolism, excretion, and storage of steroids, which account for steroid... (Review)
Review
Sulfation and desulfation of steroids are opposing processes that regulate the activation, metabolism, excretion, and storage of steroids, which account for steroid homeostasis. Steroid sulfation and desulfation are catalyzed by cytosolic sulfotransferase and steroid sulfatase, respectively. By modifying and regulating steroids, cytosolic sulfotransferase (SULT) and steroid sulfatase (STS) are also involved in the pathophysiology of steroid-related diseases, such as hormonal dysregulation, metabolic disease, and cancer. The estrogen sulfotransferase (EST, or SULT1E1) is a typical member of the steroid SULTs. This review is aimed to summarize the roles of SULT1E1 and STS in steroid homeostasis and steroid-related diseases.
Topics: Humans; Steryl-Sulfatase; Sulfotransferases; Neoplasms; Steroids; Homeostasis; Metabolic Diseases
PubMed: 37951289
DOI: 10.1016/j.steroids.2023.109335