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Cell Research Dec 2023Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear....
Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDME or GSDME knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.
Topics: Humans; Animals; Mice; Pyroptosis; Mannose; AMP-Activated Protein Kinases; Gasdermins
PubMed: 37460805
DOI: 10.1038/s41422-023-00848-6 -
Science (New York, N.Y.) Oct 2023Targeted protein degradation can provide advantages over inhibition approaches in the development of therapeutic strategies. Lysosome-targeting chimeras (LYTACs) harness...
Targeted protein degradation can provide advantages over inhibition approaches in the development of therapeutic strategies. Lysosome-targeting chimeras (LYTACs) harness receptors, such as the cation-independent mannose 6-phosphate receptor (CI-M6PR), to direct extracellular proteins to lysosomes. In this work, we used a genome-wide CRISPR knockout approach to identify modulators of LYTAC-mediated membrane protein degradation in human cells. We found that disrupting retromer genes improved target degradation by reducing LYTAC recycling to the plasma membrane. Neddylated cullin-3 facilitated LYTAC-complex lysosomal maturation and was a predictive marker for LYTAC efficacy. A substantial fraction of cell surface CI-M6PR remains occupied by endogenous M6P-modified glycoproteins. Thus, inhibition of M6P biosynthesis increased the internalization of LYTAC-target complexes. Our findings inform design strategies for next-generation LYTACs and elucidate aspects of cell surface receptor occupancy and trafficking.
Topics: Humans; HeLa Cells; Lysosomes; Membrane Proteins; Proteolysis; Receptor, IGF Type 2; Cullin Proteins; Proteolysis Targeting Chimera
PubMed: 37856615
DOI: 10.1126/science.adf6249 -
IScience Nov 2023Decidualization of endometrial stromal cells is a hallmark of endometrial receptivity for embryo implantation, and dysfunctional decidualization is associated with...
Decidualization of endometrial stromal cells is a hallmark of endometrial receptivity for embryo implantation, and dysfunctional decidualization is associated with pregnancy failure. Protein glycosylation is an important posttranslational modification that affects the structure and function of glycoproteins. Our results showed that high-mannose epitopes were elevated in the decidual tissues of miscarriage patients compared with early pregnant women by Lectin microarray. Furthermore, the level of mannosyl-oligosaccharide α-1,2 mannosidase IA (MAN1A1), a key enzyme for high-mannose glycan biosynthesis, was decreased in the decidual tissues of miscarriage patients. Screening of lncRNAs showed that lncNEAT1 level was increased in the serum and decidua of miscarriage patients, and negatively correlated with MAN1A1 expression. The results also revealed that specific binding of lncNEAT1 with nucleophosmin (NPM1)-SP1 transcription complex inhibited MAN1A1 expression and hampered endometrial decidualization and embryo implantation potential. The study suggests the new insights into the function of high-mannose glycans/MAN1A1 modification during endometrial decidualization.
PubMed: 37915610
DOI: 10.1016/j.isci.2023.108170 -
Nature Communications Mar 2024Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered...
Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered immunometabolic response cascade and reduces tissue damage. Safe and inexpensive D-mannose can compete with glucose for the same transporter and hexokinase. Such competitions suppress glycolysis, reduce mitochondrial reactive-oxygen-species and succinate-mediated hypoxia-inducible factor-1α, and thus reduce virus-induced proinflammatory cytokine production. The combinatorial treatment by D-mannose and antiviral monotherapy exhibits in vivo synergy despite delayed antiviral treatment in mouse model of virus infections. Phosphomannose isomerase (PMI) knockout cells are viable, whereas addition of D-mannose to the PMI knockout cells blocks cell proliferation, indicating that PMI activity determines the beneficial effect of D-mannose. PMI inhibition suppress a panel of virus replication via affecting host and viral surface protein glycosylation. However, D-mannose does not suppress PMI activity or virus fitness. Taken together, PMI-centered therapeutic strategy clears virus infection while D-mannose treatment reprograms glycolysis for control of collateral damage.
Topics: Animals; Mice; Mannose-6-Phosphate Isomerase; Glycosylation; Mannose; Glucose; Antiviral Agents
PubMed: 38459021
DOI: 10.1038/s41467-024-46415-4 -
International Journal of Molecular... Jan 2024The mannose receptor (MR, CD 206) is an endocytic receptor primarily expressed by macrophages and dendritic cells, which plays a critical role in both endocytosis and... (Review)
Review
The mannose receptor (MR, CD 206) is an endocytic receptor primarily expressed by macrophages and dendritic cells, which plays a critical role in both endocytosis and antigen processing and presentation. MR carbohydrate recognition domains (CRDs) exhibit a high binding affinity for branched and linear oligosaccharides. Furthermore, multivalent mannose presentation on the various templates like peptides, proteins, polymers, micelles, and dendrimers was proven to be a valuable approach for the selective and efficient delivery of various therapeutically active agents to MR. This review provides a detailed account of the most relevant and recent aspects of the synthesis and application of mannosylated bioactive formulations for MR-mediated delivery in treatments of cancer and other infectious diseases. It further highlights recent findings related to the necessary structural features of the mannose-containing ligands for successful binding to the MR.
Topics: Mannose Receptor; Mannose; Receptors, Cell Surface; Mannose-Binding Lectins; Lectins, C-Type; Ligands
PubMed: 38338648
DOI: 10.3390/ijms25031370 -
Science Translational Medicine Jan 2024Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis. TNBCs with high homologous recombination deficiency (HRD)...
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis. TNBCs with high homologous recombination deficiency (HRD) scores benefit from DNA-damaging agents, including platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, whereas those with low HRD scores still lack therapeutic options. Therefore, we sought to exploit metabolic alterations to induce HRD and sensitize DNA-damaging agents in TNBCs with low HRD scores. We systematically analyzed TNBC metabolomics and identified a metabolite, guanosine diphosphate (GDP)-mannose (GDP-M), that impeded homologous recombination repair (HRR). Mechanistically, the low expression of the upstream enzyme GDP-mannose-pyrophosphorylase-A (GMPPA) led to the endogenous up-regulation of GDP-M in TNBC. The accumulation of GDP-M in tumor cells further reduced the interaction between breast cancer susceptibility gene 2 (BRCA2) and ubiquitin-specific peptidase 21 (USP21), which promoted the ubiquitin-mediated degradation of BRCA2 to inhibit HRR. Therapeutically, we illustrated that the supplementation of GDP-M sensitized DNA-damaging agents to impair tumor growth in both in vitro (cancer cell line and patient-derived organoid) and in vivo (xenograft in immunodeficient mouse) models. Moreover, the combination of GDP-M with DNA-damaging agents activated STING-dependent antitumor immunity in immunocompetent syngeneic mouse models. Therefore, GDP-M supplementation combined with PARP inhibition augmented the efficacy of anti-PD-1 antibodies. Together, these findings suggest that GDP-M is a crucial HRD-related metabolite and propose a promising therapeutic strategy for TNBCs with low HRD scores using the combination of GDP-M, PARP inhibitors, and anti-PD-1 immunotherapy.
Topics: Animals; Mice; Humans; Triple Negative Breast Neoplasms; Recombinational DNA Repair; Mannose; Poly(ADP-ribose) Polymerase Inhibitors; Homologous Recombination; Guanosine Diphosphate Mannose; BRCA1 Protein; DNA; Ubiquitin Thiolesterase
PubMed: 38170790
DOI: 10.1126/scitranslmed.adg7740 -
Antiviral Research Jul 2024Growing concerns regarding the emergence of highly transmissible viral diseases highlight the urgent need to expand the repertoire of antiviral therapeutics. For this... (Review)
Review
Growing concerns regarding the emergence of highly transmissible viral diseases highlight the urgent need to expand the repertoire of antiviral therapeutics. For this reason, new strategies for neutralizing and inhibiting these viruses are necessary. A promising approach involves targeting the glycans present on the surfaces of enveloped viruses. Lectins, known for their ability to recognize specific carbohydrate molecules, offer the potential for glycan-targeted antiviral strategies. Indeed, numerous studies have reported the antiviral effects of various lectins of both endogenous and exogenous origins. However, many lectins in their natural forms, are not suitable for use as antiviral therapeutics due to toxicity, other unfavorable pharmacological effects, and/or unreliable manufacturing sources. Therefore, improvements are crucial for employing lectins as effective antiviral therapeutics. A novel approach to enhance lectins' suitability as pharmaceuticals could be the generation of recombinant lectin-Fc fusion proteins, termed "lectibodies." In this review, we discuss the scientific rationale behind lectin-based antiviral strategies and explore how lectibodies could facilitate the development of new antiviral therapeutics. We will also share our perspective on the potential of these molecules to transcend their potential use as antiviral agents.
Topics: Antiviral Agents; Humans; Lectins; Animals; Virus Diseases; Polysaccharides; Recombinant Fusion Proteins; Immunoglobulin Fc Fragments; Viruses
PubMed: 38734211
DOI: 10.1016/j.antiviral.2024.105901 -
Biomolecules Jan 2024While extensive research highlighted the involvement of metabolism and immune cells in female reproductive diseases, causality remains unestablished. (Meta-Analysis)
Meta-Analysis
BACKGROUND
While extensive research highlighted the involvement of metabolism and immune cells in female reproductive diseases, causality remains unestablished.
METHODS
Instrumental variables for 486 circulating metabolites ( = 7824) and 731 immunophenotypes ( = 3757) were derived from a genome-wide association study (GWAS) meta-analysis. FinnGen contributed data on 14 female reproductive disorders. A bidirectional two-sample Mendelian randomization study was performed to determine the relationships between exposures and outcomes. The robustness of results, potential heterogeneity, and horizontal pleiotropy were examined through sensitivity analysis.
RESULTS
High levels of mannose were found to be causally associated with increased risks of gestational diabetes (GDM) (OR [95% CI], 6.02 [2.85-12.73], = 2.55 × 10). A genetically predicted elevation in the relative count of circulating CD28CD25CD8 T cells was causally related to increased female infertility risk (OR [95% CI], 1.26 [1.14-1.40], = 1.07 × 10), whereas a high absolute count of NKT cells reduced the risk of ectopic pregnancy (OR [95% CI], 0.87 [0.82-0.93], = 5.94 × 10). These results remained consistent in sensitivity analyses.
CONCLUSIONS
Our study supports mannose as a promising GDM biomarker and intervention target by integrating metabolomics and genomics.
Topics: Pregnancy; Humans; Female; CD8-Positive T-Lymphocytes; Genome-Wide Association Study; Mannose; Mendelian Randomization Analysis; CD28 Antigens; Diabetes, Gestational
PubMed: 38254716
DOI: 10.3390/biom14010116 -
Frontiers in Immunology 2023The immune system starts to develop early in embryogenesis. However, at birth it is still immature and associated with high susceptibility to infection. Adaptation to... (Review)
Review
The immune system starts to develop early in embryogenesis. However, at birth it is still immature and associated with high susceptibility to infection. Adaptation to extrauterine conditions requires a balance between colonization with normal flora and protection from pathogens. Infections, oxidative stress and invasive therapeutic procedures may lead to transient organ dysfunction or permanent damage and perhaps even death. Newborns are primarily protected by innate immune mechanisms. Collectins (mannose-binding lectin, collectin-10, collectin-11, collectin-12, surfactant protein A, surfactant protein D) and ficolins (ficolin-1, ficolin-2, ficolin-3) are oligomeric, collagen-related defence lectins, involved in innate immune response. In this review, we discuss the structure, specificity, genetics and role of collectins and ficolins in neonatal health and disease. Their clinical associations (protective or pathogenic influence) depend on a variety of variables, including genetic polymorphisms, gestational age, method of delivery, and maternal/environmental microflora.
Topics: Infant, Newborn; Humans; Collectins; Ficolins; Infant Health; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein D
PubMed: 38193083
DOI: 10.3389/fimmu.2023.1328658