Affinage

STX8

Syntaxin-8 · UniProt Q9UNK0

Length
236 aa
Mass
26.9 kDa
Annotated
2026-06-10
76 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 3/3 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STX8 (syntaxin 8) is a t-SNARE of the vesicular trafficking machinery, defined by a C-terminal SNARE coiled-coil domain and a hydrophobic transmembrane anchor (PMID:10198254). It localizes to the trans-Golgi network and prevacuolar/late endosomes, where its SNARE domain drives membrane fusion; following fusion at the prevacuolar endosome, STX8 is recycled back to the TGN as a Snx3-retromer cargo, recognized via an unstructured IEMxxM sorting motif (residues I133, E134, M135, M138) distinct from its transmembrane helix (PMID:33788833). In endosome-to-lysosome fusion, STX8 acts together with VTI1B and VAMP8 [PMID:bio_10.1101_2024.12.16.627577]. This same machinery is co-opted by intracellular pathogens: the M. tuberculosis glycolipid trehalose dimycolate binds STX8 and redirects it and VTI1B into a non-canonical complex with VAMP2 at the expense of VAMP8 binding, blocking phagosome maturation and favoring bacterial replication [PMID:bio_10.1101_2024.12.16.627577]. Beyond these functions, STX8 participates in VAMP4-dependent autophagic secretion of mitochondria that drives immunosuppressive macrophage polarization in hypoxic tumour cells (PMID:41979085).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1999 Medium

    Establishing the molecular identity of STX8 was the first step: cloning revealed a protein with the domain hallmarks of the t-SNARE family, placing an otherwise uncharacterized gene into the vesicle docking/fusion machinery.

    Evidence Yeast two-hybrid cloning using the CFTR R domain as bait, sequence/domain analysis, and chromosomal mapping

    PMID:10198254

    Open questions at the time
    • Function inferred from domain architecture, not tested in a fusion assay
    • Subcellular localization not established
    • The functional significance of the CFTR R-domain interaction was not pursued
  2. 2021 High

    How STX8 is localized and maintained at its compartment was resolved by showing it functions at the TGN/prevacuolar endosome and is retrieved by retromer through a discrete sorting signal, defining both its site of action and its recycling itinerary.

    Evidence Mutagenesis, live-cell imaging, and retromer/sorting-nexin epistasis with phenotypic readout in S. pombe

    PMID:33788833

    Open questions at the time
    • Identity of the cognate SNARE partners at the PVE in this system not defined
    • Conservation of the IEMxxM signal and Snx3-retromer dependence in mammalian cells not directly tested
    • Structural basis of retromer recognition of the motif unknown
  3. 2024 Medium

    The cognate SNARE partnerships of STX8 in endosome fusion and the mechanism of pathogen subversion were addressed by showing STX8/VTI1B normally fuse with VAMP8 but are diverted to VAMP2 by a mycobacterial glycolipid, explaining how phagosome maturation is blocked.

    Evidence Photoaffinity TDM probe pulldown/MS, SNARE Co-IP, phagosome maturation and intracellular replication assays in macrophages (preprint)

    PMID:bio_10.1101_2024.12.16.627577

    Open questions at the time
    • Not yet peer-reviewed
    • Direct fusion reconstitution of the canonical vs non-canonical complexes not shown
    • Whether STX8 is a direct TDM-binding partner versus a complex co-member not fully resolved
  4. 2024 Low

    A second pathogen route was probed by identifying STX8 as an interactor of the Salmonella effector SipA and a component recruited to the Salmonella-containing vacuole, implicating its fusion machinery in vacuolar niche maintenance.

    Evidence BioID proximity labeling and live-cell imaging of SCV biogenesis (preprint)

    PMID:bio_10.1101_2024.12.12.628128

    Open questions at the time
    • Interaction from a screen without direct functional validation of STX8 by KD/KO
    • Not independently confirmed and not peer-reviewed
    • Mechanism by which STX8 maintains the SCV not established
  5. 2026 Medium

    A role beyond classical endosomal fusion was established by showing STX8, with VAMP4, mediates autophagic secretion of mitochondria that reshapes the tumour immune microenvironment, linking SNARE-dependent secretion to immunosuppression.

    Evidence Multivesicular body membrane proteomics, interaction validation, EV characterization, and macrophage polarization assays in a hypoxic HNSCC model

    PMID:41979085

    Open questions at the time
    • Single lab; direct fusion mechanism for mitochondrial secretion not reconstituted
    • Whether STX8 directly pairs with VAMP4 versus acting in a larger complex not resolved
    • Generality beyond hypoxic HNSCC not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full complement of STX8 SNARE pairings across compartments, the structural basis of its complex assembly, and whether its mammalian recycling mirrors the S. pombe retromer mechanism remain open.
  • No structural model of STX8-containing SNARE complexes
  • Mammalian retromer dependence and IEMxxM conservation untested
  • Quantitative contributions of canonical vs non-canonical partners not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005768 endosome 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3
Partners
SIPAVAMP2VAMP4VAMP8VTI1B

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Human syntaxin 8 (STX8) was cloned by yeast two-hybrid screening using the R domain of CFTR as bait; the encoded 236-amino-acid protein contains a C-terminal coiled-coil domain conserved in the t-SNARE superfamily and a C-terminal hydrophobic transmembrane anchor, placing it in the vesicular trafficking/docking machinery. Yeast two-hybrid screening of human fetal lung cDNA library; sequence analysis; chromosomal mapping to 17p12 Biochemical and biophysical research communications Medium 10198254
2021 S. pombe Stx8 (ortholog of mammalian syntaxin 8) localizes to the trans-Golgi network (TGN) and prevacuolar endosome (PVE) and is required for vesicle fusion at the PVE; its SNARE domain is essential for function. Stx8 recycling from the PVE back to the TGN depends on the retromer component Vps35 and sorting nexins Vps5, Vps17, and Snx3, identifying it as a Snx3-retromer cargo. A sorting signal (IEMeaM, with residues I133, E134, M135, M138 all essential) in an unstructured region distant from the transmembrane helix mediates retromer recognition. Deletion and alanine-scanning mutagenesis; live-cell fluorescence microscopy; genetic epistasis with retromer/sorting nexin mutants; salt-sensitivity phenotyping of stx8Δ cells PLoS genetics High 33788833
2024 Trehalose dimycolate (TDM), the abundant M. tuberculosis envelope glycolipid, physically binds STX8 (along with VTI1B and VAMP2) as detected by a clickable photoaffinity TDM probe. Normally, VTI1B and STX8 promote endosome fusion by complexing with VAMP8; however, in the presence of M. tuberculosis, VTI1B and STX8 instead complex non-canonically with VAMP2, reducing VAMP8 binding, inhibiting phagosome maturation, and promoting intracellular M. tuberculosis replication. Clickable photoaffinity TDM probe pulldown/MS in macrophages; co-immunoprecipitation of SNARE complexes; functional phagosome maturation assay; intracellular bacterial replication assay bioRxivpreprint Medium bio_10.1101_2024.12.16.627577
2024 Salmonella Typhimurium effector protein SipA interacts with STX8, and STX8 is recruited to Salmonella-containing vacuoles (SCVs); this interaction is proposed to maintain the vacuolar niche by engaging host endosomal fusion machinery. BioID proximity labeling screening (identified STX8–SipA interaction); live-cell imaging of SCV biogenesis bioRxivpreprint Low bio_10.1101_2024.12.12.628128
2026 Under hypoxic conditions in head and neck squamous cell carcinoma (HNSCC), STX8 and VAMP4 are key mediators of mitophagy-dependent extracellular vesicle (EV) secretion. STX8 participates in the autophagic secretion of mitochondria, and this SNARE-dependent process promotes polarization of tumour-associated macrophages toward an immunosuppressive phenotype, reshaping the tumour immune microenvironment. Multivesicular body membrane proteomics; molecular interaction validation (co-IP/pulldown); EV characterization; macrophage polarization functional assay; HNSCC cell hypoxia model Journal of extracellular vesicles Medium 41979085

Source papers

Stage 0 corpus · 76 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1983 The carB gene of Escherichia coli: a duplicated gene coding for the large subunit of carbamoyl-phosphate synthetase. Proceedings of the National Academy of Sciences of the United States of America 155 6308632
2016 Vina-Carb: Improving Glycosidic Angles during Carbohydrate Docking. Journal of chemical theory and computation 93 26744922
1991 Construction by polymerase chain reaction and use of intragenic DNA probes for three main types of transferable beta-lactamases (TEM, SHV, CARB) [corrected]. FEMS microbiology letters 86 1936934
2012 Relatively high-protein or 'low-carb' energy-restricted diets for body weight loss and body weight maintenance? Physiology & behavior 78 22935440
2015 CARB-17 family of β-lactamases mediates intrinsic resistance to penicillins in Vibrio parahaemolyticus. Antimicrobial agents and chemotherapy 55 25801555
2002 A carotenoid biosynthesis gene cluster in Fusarium fujikuroi: the genes carB and carRA. Molecular genetics and genomics : MGG 53 12172798
2003 Carboxymethylproline synthase (CarB), an unusual carbon-carbon bond-forming enzyme of the crotonase superfamily involved in carbapenem biosynthesis. The Journal of biological chemistry 40 14625287
2009 Genetic and biochemical characterization of the first extended-spectrum CARB-type beta-lactamase, RTG-4, from Acinetobacter baumannii. Antimicrobial agents and chemotherapy 39 19380596
2004 CARB-9, a carbenicillinase encoded in the VCR region of Vibrio cholerae non-O1, non-O139 belongs to a family of cassette-encoded beta-lactamases. Antimicrobial agents and chemotherapy 39 15388476
2014 Evaluation of five chromogenic agar media and the Rosco Rapid Carb screen kit for detection and confirmation of carbapenemase production in Gram-negative bacilli. Journal of clinical microbiology 35 25355764
1990 Methylation of 23S ribosomal RNA due to carB, an antibiotic-resistance determinant from the carbomycin producer, Streptomyces thermotolerans. European journal of biochemistry 35 1691981
2002 New carbenicillin-hydrolyzing beta-lactamase (CARB-7) from Vibrio cholerae non-O1, non-O139 strains encoded by the VCR region of the V. cholerae genome. Antimicrobial agents and chemotherapy 34 12069969
2000 Identification of CIP-1-associated regulator of cyclin B (CARB), a novel p21-binding protein acting in the G2 phase of the cell cycle. The Journal of biological chemistry 29 10781590
1998 The carB gene encoding the large subunit of carbamoylphosphate synthetase from Lactococcus lactis is transcribed monocistronically. Journal of bacteriology 27 9721272
2005 Analysis of mating-dependent transcription of Blakeslea trispora carotenoid biosynthesis genes carB and carRA by quantitative real-time PCR. Applied microbiology and biotechnology 25 15744487
2004 Operator design and mechanism for CarA repressor-mediated down-regulation of the photoinducible carB operon in Myxococcus xanthus. The Journal of biological chemistry 24 15123730
2000 Nucleotide sequence of the bla(RTG-2) (CARB-5) gene and phylogeny of a new group of carbenicillinases. Antimicrobial agents and chemotherapy 24 10722515
1999 Molecular cloning, expression analysis, and chromosomal localization of human syntaxin 8 (STX8). Biochemical and biophysical research communications 23 10198254
1999 Characterization and nucleotide sequence of CARB-6, a new carbenicillin-hydrolyzing beta-lactamase from Vibrio cholerae. Antimicrobial agents and chemotherapy 23 9925522
2006 Low-carb diets, fasting and euphoria: Is there a link between ketosis and gamma-hydroxybutyrate (GHB)? Medical hypotheses 22 17011713
2014 A case of IMP-4-, OXA-421-, OXA-96-, and CARB-2-producing Acinetobacter pittii sequence type 119 in Australia. Journal of clinical microbiology 21 25428154
1998 Structure of CARB-4 and AER-1 carbenicillin-hydrolyzing beta-lactamases. Antimicrobial agents and chemotherapy 21 9687391
2015 Molecular study on the carAB operon reveals that carB gene is required for swimming and biofilm formation in Xanthomonas citri subsp. citri. BMC microbiology 20 26494007
2014 Thio-sugar motif of functional CARB-pharmacophore for antineoplastic activity. Part 2. Bioorganic & medicinal chemistry letters 19 25466184
1989 Novel carbenicillin-hydrolyzing beta-lactamase (CARB-5) from Acinetobacter calcoaceticus var. anitratus. FEMS microbiology letters 19 2786828
2017 MDD-carb: a combinatorial model for the identification of protein carbonylation sites with substrate motifs. BMC systems biology 17 29322938
2023 Effects of the low-carb organic Mediterranean diet on testosterone levels and sperm DNA fragmentation. Current research in food science 16 38045510
2021 Rapid and Visual Detection of Vibrio parahaemolyticus in Aquatic Foods Using blaCARB-17 Gene-Based Loop-Mediated Isothermal Amplification with Lateral Flow Dipstick (LAMP-LFD). Journal of microbiology and biotechnology 16 34489378
2014 A potential CARB-pharmacophore for antineoplastic activity: part 1. Bioorganic & medicinal chemistry letters 15 24602905
2021 Retrospective cohort study of changes in estimated glomerular filtration rate for patients prescribed a low carb diet. Current opinion in endocrinology, diabetes, and obesity 12 34392262
2021 Changes in Quantity and Sources of Dietary Fiber from Adopting Healthy Low-Fat vs. Healthy Low-Carb Weight Loss Diets: Secondary Analysis of DIETFITS Weight Loss Diet Study. Nutrients 10 34684626
2014 Carb-3 is the superior anti-CD15 monoclonal antibody for immunohistochemistry. Applied immunohistochemistry & molecular morphology : AIMM 10 23846425
2023 A low-carb diet increases fecal short-chain fatty acids in feces of obese women following a weight-loss program: randomized feeding trial. Scientific reports 9 37875472
2020 Carb-Loading: Freeze-Induced Activation of the Glucose-Responsive ChREBP Transcriptional Network in Wood Frogs. Physiological and biochemical zoology : PBZ 9 31742477
2020 Effects of a Low Carb Diet and Whey Proteins on Anthropometric, Hematochemical, and Cardiovascular Parameters in Subjects with Obesity. Endocrine, metabolic & immune disorders drug targets 9 32520693
2017 A novel GoldNano Carb test for rapid phenotypic detection of carbapenemases, particularly OXA type, in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. The Journal of antimicrobial chemotherapy 9 28535303
1999 Heterologous expression of the Phycomyces blakesleeanus phytoene dehydrogenase gene (carB) in Mucor circinelloides. Current microbiology 9 10489434
2023 Rapid generation of CD19 CAR-T cells by minicircle DNA enables anti-tumor activity and prevents fatal CAR-B leukemia. Cancer letters 8 37354981
2020 Structural analysis of the CARB β-lactamase from Vibrio parahaemolyticus facilitates application of the β-lactam/β-lactamase inhibitor therapy. Biochimie 8 32179166
2008 Campylobacter jejuni host tissue tropism: a consequence of its low-carb lifestyle? Cell host & microbe 8 18996338
1997 Identification of greA encoding a transcriptional elongation factor as a member of the carA-orf-carB-greA operon in Pseudomonas aeruginosa PAO1. Journal of bacteriology 8 9139926
2022 SPINA Carb: a simple mathematical model supporting fast in-vivo estimation of insulin sensitivity and beta cell function. Scientific reports 7 36271244
2023 Centrally acting ACE inhibitor (cACEi) and angiotensin receptor blocker (cARB) use and cognitive dysfunction in patients with SLE. Lupus science & medicine 6 37429671
2022 Nutritional Quality of Gluten-Free Bakery Products Labeled Ketogenic and/or Low-Carb Sold in the Global Market. Foods (Basel, Switzerland) 6 36553837
2013 Specific discrimination of three pathogenic Salmonella enterica subsp. enterica serotypes by carB-based oligonucleotide microarray. Applied and environmental microbiology 6 24185846
2010 Protein-DNA interactions in the promoter region of the Phycomyces carB and carRA genes correlate with the kinetics of their mRNA accumulation in response to light. Fungal genetics and biology : FG & B 6 20580936
1995 Induction of protein oxidation in human low density lipoprotein by the photosensitive organic hydroperoxide, N,N'-bis(2-hydroxyperoxy-2-methoxyethyl)-1,4,5,8-naphthalene-tetra-carb oxylic- diimide. Biochemical and biophysical research communications 6 7818513
2015 Diversity of Rhodopirellula and related planctomycetes in a North Sea coastal sediment employing carB as molecular marker. FEMS microbiology letters 5 26253575
2008 Fly-let biology and the high protein/low carb diet. Cell metabolism 5 18396131
2019 A highly resistant structure between the cuticle and the cortex of human hair. II. CARB, a penetration barrier. International journal of cosmetic science 4 30549286
2024 Short-term high-fat and high-carb diet effects on glucose metabolism and hedonic regulation in young healthy men. Frontiers in nutrition 3 39534438
2021 Analysis of the SNARE Stx8 recycling reveals that the retromer-sorting motif has undergone evolutionary divergence. PLoS genetics 3 33788833
2021 The effect of high-fat versus high-carb diet on body composition in strength-trained males. Food science & nutrition 3 34026070
2021 Custard apple puree, fructooligosaccharide and soy protein hydrolysate as alternative ingredients in low carb pound cake. Journal of food science and technology 3 34366480
2021 Low-carb Diet in Hospitalized Late Pubertal Type 1 Diabetic Girls: A Short-Term CGM Study. Indian journal of endocrinology and metabolism 3 34386391
2018 [Analyses on distribution and structure of blaCARB-2 in Klebsiella pneumoniae]. Yi chuan = Hereditas 3 30021722
2024 Synthesis of 2-Amino-N'-aroyl(het)arylhydrazides, DNA Photocleavage, Molecular Docking and Cytotoxicity Studies against Melanoma CarB Cell Lines. Molecules (Basel, Switzerland) 2 38338390
2021 A new tetra-kis-substituted pyrazine carb-oxy-lic acid, 3,3',3'',3'''-{[pyrazine-2,3,5,6-tetra-yltetra-kis(methyl-ene)]tetra-kis-(sulfanedi-yl)}tetra-propionic acid: crystal structures of two triclinic polymorphs and of two potassium-organic frameworks. Acta crystallographica. Section E, Crystallographic communications 2 34026250
2012 Glycosyltransferases: carb loading strategy is spot on. Nature chemical biology 2 22907089
2010 4-(4-Pyrid-yl)pyridinium 3-amino-5-carb-oxy-2,4,6-triiodo-benzoate-5-amino-2,4,6-triiodo-isophthalic acid (1/1). Acta crystallographica. Section E, Structure reports online 2 21589461
2002 Should you recommend a low-carb, high-protein diet? The Nurse practitioner 2 11984418
2025 Crystal structure, Hirshfeld surface analysis, DFT and mol-ecular docking studies of 4'-(benz-yloxy)-[1,1'-biphen-yl]-3-carb-oxy-lic acid. Acta crystallographica. Section E, Crystallographic communications 1 40071035
2025 Associations of low-carb diets with glycaemic control and diabetic complications among adult Ghanaians: the RODAM study. European journal of nutrition 1 40481960
2025 Distribution and Evolutionary Trajectories of β-Lactamases in Vibrio: Genomic Insights from Carbenicillin-Hydrolyzing Class A β-Lactamases (CARB) in the Harveyi and Cholerae Clades. Genome biology and evolution 1 40556499
2025 The Role of Diet and Hormones on Taste: Low Carb Compared With Low Fat Study Findings. Current developments in nutrition 1 40606290
2025 Modulation of Gut Bacterial and Fungal Microbiota in Fibromyalgia Patients Following a Carb-Free Oloproteic Diet: Evidence for Candida Suppression and Symptom Improvement. Microorganisms 1 41011401
2021 A highly resistant structure between the cuticle and the cortex of human hair III: Characterzation of the structure CARB. International journal of cosmetic science 1 33527469
2021 The carB Gene of Escherichia coli BL21(DE3) is Associated with Nematicidal Activity against the Root-Knot Nematode Meloidogyne javanica. Pathogens (Basel, Switzerland) 1 33670696
2018 Carb loading takes proteins on a ride. The Journal of biological chemistry 1 29626108
2014 Crystal structure of 9-(4-bromo-but-yl)-9H-fluorene-9-carb-oxy-lic acid. Acta crystallographica. Section E, Structure reports online 1 25484705
2012 catena-Poly[[[bis-[μ-3-(4-carb-oxy-phen-oxy)propionato]-κO,O:O;κO:O,O-bis-[aqua-(N,N-dimethyl-formamide-κO)cadmium]]-μ-4,4'-bipyridine-κN:N'] dinitrate]. Acta crystallographica. Section E, Structure reports online 1 22346877
2026 VAMP4/STX8 Mediate the Autophagic Secretion of Mitochondria and Promote TAMs Polarization in HNSCC. Journal of extracellular vesicles 0 41979085
2025 Deciphering the Role of VIM, STX8, and MIF in Pneumoconiosis Susceptibility: A Mendelian Randomization Analysis of the Lung-Gut Axis and Multi-Omics Insights from European and East Asian Populations. Biomedical and environmental sciences : BES 0 41196107
2021 Current Evidence Regarding Low-carb Diets for The Metabolic Control of Type-2 Diabetes. Current diabetes reviews 0 33231159
2020 [The content of essential and toxic microelements in the organs of mice of various lines receiving a high-carb high-fat diet and supplemented with quercetin]. Voprosy pitaniia 0 32459903
2012 The attachment disorders of muscle: failure to carb-load. The Journal of clinical investigation 0 22922262

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