bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2026–03–15
seven papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Redesigning chondroitin 6-O-sulfotransferase for efficient whole-cell biosynthesis of chondroitin sulfate C.
  2. An anticoagulant activity and protein interaction study of chondroitin sulfate-coated magnetic nanocomposites.
  3. A novel TGFβ1-Hs3st2-tau axis regulates tau pathology and synaptic integrity.
  4. Electric Method for the Desulfation of Polysaccharides From Red Microalgae (Porphyridium cruentum) Cultures.
  5. An antibody-drug conjugate designed through clone and isotype selection restricts the growth of CSPG4-expressing triple-negative breast cancer.
  6. Evaluation of risk promoting effects for age-related macular degeneration by estradiol.
  7. Emerging molecular mechanisms of cGAS-STING activation and regulation.
  1. Bioresour Technol. 2026 Mar 11. pii: S0960-8524(26)00478-5. [Epub ahead of print] 134397
    Redesigning chondroitin 6-O-sulfotransferase for efficient whole-cell biosynthesis of chondroitin sulfate C.
    Weiwei Meng, Mengjian Gao, Lulu Li, Liming Liu, Xiaomin Li, Wanqing Wei, Jing Wu.
      Osteoarthritis remains a global health problem and chondroitin sulfate C (CSC) is effective to treat arthritis. The biosynthesis of CSC offers a sustainable and promising alternative to conventional extraction from animal tissues. However, the scarcity of chondroitin-6-O-sulfotransferases and their low catalytic performance have severely hindered the large-scale biosynthesis of CSC. To overcome these limitations, a novel chondroitin-6-O-sulfotransferase from Rattus norvegicus (RnCHST3) was identified via gene fishing, which demonstrates regioselectivity in transferring a sulfate group from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to the 6-position of chondroitin. Subsequent optimization of expression conditions and truncation of the N-terminal region enhanced the sulfation rate from 4.6% to 11.5%. For the first time, the regioselective mechanism of RnCHST3 was elucidated through molecular dynamics (MD) simulations and site-directed mutagenesis. A mechanism-guided rational design led to the development of mutant M5, which increased the sulfation rate to 46.2%. Furthermore, a novel "physical sieve"-guided PROSS design was developed to improve kinetic thermostability, resulting in mutant M7. This variant exhibited an extended half-life from 9.4 h to 12.3 h and achieved a sulfation rate to 74.5%. Finally, a whole-cell catalytic system was constructed for CSC production, reaching a sulfation rate of 86.4% and a titer of 12.9 g·L-1-the highest level reported to date. This study lays a solid foundation for the industrial biosynthesis of CSC.
    Keywords:  Chondroitin 6-O-sulfotransferase; Chondroitin sulfate C; Protein engineering; Sulfation rate; Whole-cell biosynthesis
    DOI:  https://doi.org/10.1016/j.biortech.2026.134397
  2. Int J Biol Macromol. 2026 Mar 10. pii: S0141-8130(26)01307-3. [Epub ahead of print] 151381
    An anticoagulant activity and protein interaction study of chondroitin sulfate-coated magnetic nanocomposites.
    Matej Bračič, Matjaž Rantaša, Lidija Fras Zemljič, Matjaž Finšgar, Marjana Simonič, Sašo Gyergyek, Josip Radić, Olivija Plohl.
      Intravascular thrombosis is a significant cause of morbidity and mortality worldwide, highlighting the need for safe and effective anticoagulants. Chondroitin sulfate (CSul) has a weaker antithrombotic effect than heparin, but has a significantly lower bleeding risk, making it an attractive anticoagulant for the next generation of therapeutics. Here, we report for the first time the development of magnetically responsive anticoagulant nanocomposites prepared by functionalizing CSul on the surface of iron oxide magnetic nanoparticles (MNPs). The iron oxide MNPs were prepared by co-precipitation, and then functionalized with CSul at an elevated temperature to add the negatively charged functional groups that exhibit anticoagulant potential. Comprehensive pHysicochemical characterization, including transmission and scanning electron microscopy, X-ray diffraction, attenuated total reflectance Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, zeta potential as a function of pH, dynamic light scattering, thermogravimetry, and magnetometry, confirmed the presence of the CSul coating on the MNPs. The stability of the CSul coating was determined at physiologically relevant pH values, which revealed minor desorption of the polysaccharides. The hemocompatibility was investigated using the activated partial thromboplastin time and solid-liquid interaction tests with a key coagulation protein, i.e., bovine fibrinogen. The hemocompatibility studies showed that the MNPs@CSul prolonged clotting time compared to bare MNPs and exhibited reduced fibrinogen adsorption, consistent with partial anticoagulant and antifouling properties. Overall, these findings establish proof-of-concept that CSul-coated MNPs combine anticoagulant activity with magnetic manipulability. This dual functionality underlines their potential as a platform for externally guided antithrombotic therapies with a lower risk of bleeding.
    Keywords:  Chondroitin sulfate; Magnetic nanoparticles; Solid-liquid interactions
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.151381
  3. Front Neurosci. 2025 ;19 1726022
    A novel TGFβ1-Hs3st2-tau axis regulates tau pathology and synaptic integrity.
    Rafael Castillo-Negrete, Heloise Merrick, Sethupathiraj Selvaraj, Minh Bao Huynh, Xavier Laffray, Ajitha Thuraisamy, Martin Diener, Peter Jedlicka, Mohand Ouidir Ouidja, Dulce Papy-Garcia.
       Introduction: Tauopathies are a group of neurodegenerative diseases characterized by the pathological accumulation of tau protein. The hippocampus, a brain region crucial for learning and memory, is particularly susceptible to tau-induced damage. However, the molecular mechanisms underlying this vulnerability remain poorly understood. Here, we identified a novel TGFβ1-HS3ST2-tau signaling axis involved in tau pathology and synaptic impairment.
    Methods: We used primary hippocampal neurons from a transgenic mouse model of tauopathy to investigate the relevance of TGFβ1 signaling on Hs3st expression and tau pathology. Loss-of-function (LOF) experiments targeting the neural Hs3st2 were conducted and cells were analyzed using transcriptomics, immunoblotting, and immunohistochemistry.
    Results: TGFβ1 signaling enhanced Hs3st gene expression, linking neuroinflammation to altered HS biosynthesis. TGFβ1 was shown to regulate tau hyperphosphorylation and oligomerization through the accumulation of 3-O-sulfated heparan sulfate (3S-HS) made by Hs3st2. Hs3st2 LOF significantly reduced 3S-HS levels, tau pathology, and synaptic alterations in hippocampal neurons.
    Discussion: These findings define a new TGFβ1-Hs3st2-tau axis in the hippocampus and highlight 3S-HS as a key modulator of tau pathology and synaptic dysfunction. Targeting this pathway may offer new therapeutic opportunities in tauopathies and related neurodegenerative disorders.
    Keywords:  AD-related tauopathy; Hs3st2; TGFβ1; neurodegeneration; synapse; tau
    DOI:  https://doi.org/10.3389/fnins.2025.1726022
  4. Biopolymers. 2026 Mar;117(2): e70087
    Electric Method for the Desulfation of Polysaccharides From Red Microalgae (Porphyridium cruentum) Cultures.
    Oshrat Levy-Ontman, Amikam Bar-Gil, Eli Shemesh, Mahmoud Huliehel, Yehudit Amor, Naama Landes, Yonatan Sadeh, Dan Tchernov.
      Sulfated polysaccharides from the red microalgae Porphyridium cruentum demonstrate unique physicochemical properties and antiviral activity. Despite growing interest, it is yet unclear how the sulfates within these polysaccharides affect their rheological properties and whether they are required for the antiviral activity. We report a nondestructive method to deplete sulfates from these polysaccharides by directly exposing the growth medium to a moderate electric field (3.43 V/cm); a 5 min exposure yielded a polysaccharide fraction around the cathode, which we collected and compared to polysaccharides extracted via a traditional, ethanol-based method. Although the electric field did not affect the sugar composition of the polysaccharide and retained its gel-like properties, it substantially reduced its sulfate content (from 5.8% to 1.2%), viscosity (by fivefold), and stiffness (by eightfold) relative to the ethanol-separated fraction. Yet, the bioactivity of the sulfate-depleted polysaccharide against Herpes simplex virus 1 was only slightly reduced (~15%), suggesting that the sulfate groups do not significantly contribute to the antiviral potency of this polysaccharide. The reported electric-field separation methods is, therefore, a simple, straightforward, and nontoxic means for the direct recovery of desulfated polysaccharides from P. cruentum cultures, yielding a low-toxicity and highly stable gel-like material with enhanced amenability for antiviral applications.
    Keywords:   Porphyridium cruentum ; HSV‐1; antiviral; desulfation; polysaccharide; sulfate
    DOI:  https://doi.org/10.1002/bip.70087
  5. NPJ Precis Oncol. 2026 Mar 07.
    An antibody-drug conjugate designed through clone and isotype selection restricts the growth of CSPG4-expressing triple-negative breast cancer.
    Benjamina Esapa, Yi Liu, Alicia M Chenoweth, Katie Stoker, Natalia Łabędź, Pablo Romero-Clavijo, Kristina M Ilieva, Jennifer Trendell, Blanca Navarro-Llinas, Erin Suriawinata, Tobias Butcher, Ning Wang, Melanie Grandits, Lais C G F Palhares, Alexandra McCraw, Silvia Crescioli, Annelie Johansson, Sheeba Irshad, Anita Grigoriadis, Patrycja Gazinska, Sophia Tsoka, Vijay Chudasama, James R Baker, Andrew N J Tutt, Anthony Cheung, David E Thurston, Sophia N Karagiannis.
      Antibody-drug conjugates (ADCs) demonstrate therapeutic potential, but aggressive triple-negative breast cancers (TNBCs) require precise target selection and antibody optimisation. We identified chondroitin sulfate proteoglycan 4 (CSPG4) expression in neoadjuvant treatment-resistant TNBC to guide ADC development. Three anti-CSPG4 IgG1 antibodies with distinct variable regions (225.28S, 763.74, and 9.2.27) were engineered and compared. 225.28S IgG1 demonstrated the most efficient internalisation and potent cancer cell cytotoxicity when conjugated to the tubulin inhibitor MMAE. To determine the optimal isotype, we generated 225.28S IgG4 and directly compared it with 225.28S IgG1. The IgG1 isotype showed superior internalisation and killing activity as an MMAE-conjugated ADC. Conjugation of 225.28S IgG1 to the topoisomerase inhibitor DXd produced an ADC with a drug-to-antibody ratio (DAR) of 8. This ADC was capable of robust internalisation into cancer cells and tumour cell cytotoxicity in vitro, and significant growth restriction of two CSPG4-expressing TNBC patient-derived xenografts (PDX) implanted orthotopically in mouse mammary fat pads. Unconjugated 225.28S IgG1 also limited TNBC xenograft growth in immunodeficient mice engrafted with human immune cells, confirming Fc-mediated functional activity. These studies identify 225.28S IgG1 as the optimal clone and isotype, supporting a next-generation DXd-conjugated ADC as a promising therapeutic strategy for hard-to-treat CSPG4-expressing TNBC.
    DOI:  https://doi.org/10.1038/s41698-026-01341-0
  6. PLoS One. 2026 ;21(3): e0340477
    Evaluation of risk promoting effects for age-related macular degeneration by estradiol.
    Inga-Marie Pompös, Dietrich Polenz, Norbert Kociok, Silvia Winkler, Olaf Strauß.
      Early menopause increases the risk for age-related macular degeneration (AMD), the most common cause of vision loss in industrialized countries. The supplementation with estradiol reduces the risk in these cases and suggesting that estradiol deficiency is a mediator of the risk association. We investigated rat models of estradiol deficiency mimicking either biological ageing (22 months of age) or early menopause by ovariectomy and age of 22 months. Serum analysis of gonadal hormones in both models showed the expected reduction in estradiol levels compared to 6 months old controls but also increases in progesterone, corticosterone and dehydroepiandrosterone sulfate (DHEA-S). Comparing the two estradiol deficiency models, we found no differences except for DHEA-S that were reduced in ovariectomized rats. The hormone status was associated with degenerative changes in the retina with higher activity of mononuclear phagocytes and p16/p21-dependent senescence. Mainly the estrogen receptor beta (ERβ) expressing cells were affected by estradiol deficiency: ganglion cells, cells of the inner nuclear layer (INL) and retinal pigment epithelial cells. An exception are photoreceptors that were ERβ negative, showed stronger degeneration in ovariectomized rats compared to sham treated animals. We conclude that either biological or ovariectomy induced estradiol deficiency might not cause but rather promote mechanisms that lead to AMD. The phenotype depends on a broader spectrum of altered hormones than on estradiol alone. Photoreceptor degeneration and cellular senescence that were ERβ independent in ovariectomized rats suggest non-estradiol effects to increase AMD risk by early menopause.
    DOI:  https://doi.org/10.1371/journal.pone.0340477
  7. Mol Immunol. 2026 Mar 09. pii: S0161-5890(26)00034-9. [Epub ahead of print]193 10-25
    Emerging molecular mechanisms of cGAS-STING activation and regulation.
    Yilin Liu, Kanglong Ma, Zhengfan Jiang.
      The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a crucial component of the innate immune system, responsible for detecting cytosolic double-stranded DNA (dsDNA) from both pathogen invasion and host damage, thereby initiating a robust type I-interferons (IFNs) response. In this review, we summarize the complex and stringent mechanisms governing the activation and regulation of the cGAS-STING pathway. We describe the structural basis of cGAS activation by dsDNA and its catalytic synthesis of 2'3'-cGAMP, and highlight the DNA-independent activation of cGAS by manganese (Mn2 +), which exhibits a distinct catalytic mechanism. We also discuss recent advances in the regulatory mechanisms of cGAS. The binding of 2'3'-cGAMP triggers STING translocation from the ER to the Golgi apparatus, where sulfated glycosaminoglycans (sGAGs) act as an essential second ligand to promote STING polymerization. Following this, a second translocation from the trans-Golgi network (TGN) to endosomes is required for its full activation. Conversely, supranormal concentrations of 2'3'-cGAMP induce the formation of ER-localized STING biocondensates, which restrict activation and thus prevent an excessive immune response. Dysregulation of the cGAS-STING pathway has been implicated in diverse human health conditions, including infection, autoimmune disorders, neurodegeneration, ageing, and cancer. Understanding these activation and regulatory mechanisms will inform the development of novel therapeutic strategies.
    Keywords:  CGAS-STING; Innate immunity; Manganese (Mn(2+)); STING phase-separator; STING trafficking; Sulfated glycosaminoglycans (sGAGs)
    DOI:  https://doi.org/10.1016/j.molimm.2026.02.008
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