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1.
Annu Rev Biochem ; 93(1): 565-601, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38640018

RESUMO

Human lectins are integral to maintaining microbial homeostasis on the skin, in the blood, and at mucosal barriers. These proteins can recognize microbial glycans and inform the host about its microbial status. In accordance with their roles, their production can vary with tissue type. They also can have unique structural and biochemical properties, and they can influence microbial colonization at sites proximal and distal to their tissue of origin. In line with their classification as innate immune proteins, soluble lectins have long been studied in the context of acute infectious disease, but only recently have we begun to appreciate their roles in maintaining commensal microbial communities (i.e., the human microbiota). This review provides an overview of soluble lectins that operate at host-microbe interfaces, their glycan recognition properties, and their roles in physiological and pathological mechanisms.


Assuntos
Imunidade Inata , Lectinas , Polissacarídeos , Humanos , Lectinas/metabolismo , Lectinas/química , Lectinas/genética , Polissacarídeos/metabolismo , Polissacarídeos/química , Microbiota , Animais , Interações Hospedeiro-Patógeno , Interações entre Hospedeiro e Microrganismos/imunologia
2.
Annu Rev Biochem ; 93(1): 529-564, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38669516

RESUMO

The complex carbohydrate structures decorating human proteins and lipids, also called glycans, are abundantly present at cell surfaces and in the secretome. Glycosylation is vital for biological processes including cell-cell recognition, immune responses, and signaling pathways. Therefore, the structural and functional characterization of the human glycome is gaining more and more interest in basic biochemistry research and in the context of developing new therapies, diagnostic tools, and biotechnology applications. For glycomics to reach its full potential in these fields, it is critical to appreciate the specific factors defining the function of the human glycome. Here, we review the glycosyltransferases (the writers) that form the glycome and the glycan-binding proteins (the readers) with an essential role in decoding glycan functions. While abundantly present throughout different cells and tissues, the function of specific glycosylation features is highly dependent on their context. In this review, we highlight the relevance of studying the glycome in the context of specific carrier proteins, cell types, and subcellular locations. With this, we hope to contribute to a richer understanding of the glycome and a more systematic approach to identifying the roles of glycosylation in human physiology.


Assuntos
Glicômica , Glicosiltransferases , Polissacarídeos , Humanos , Glicosilação , Polissacarídeos/metabolismo , Polissacarídeos/química , Glicosiltransferases/metabolismo , Glicosiltransferases/genética , Glicosiltransferases/química , Glicômica/métodos , Glicoproteínas/metabolismo , Glicoproteínas/química , Glicoproteínas/genética , Animais , Processamento de Proteína Pós-Traducional
3.
Cell ; 187(11): 2628-2632, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38788686

RESUMO

Glycans, with their variable compositions and highly dynamic conformations, vastly expand the heterogeneity of whatever factor or cell they are attached to. These properties make them crucial contributors to biological function and organismal health and also very difficult to study. That may be changing as we look to the future of glycobiology.


Assuntos
Glicômica , Polissacarídeos , Animais , Humanos , Polissacarídeos/metabolismo , Polissacarídeos/química
4.
Cell ; 187(19): 5228-5237.e12, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39173631

RESUMO

GlycoRNA consists of RNAs modified with secretory N-glycans that are presented on the cell surface. Although previous work supported a covalent linkage between RNA and glycans, the direct chemical nature of the RNA-glycan connection was not described. Here, we develop a sensitive and scalable protocol to detect and characterize native glycoRNAs. Leveraging RNA-optimized periodate oxidation and aldehyde ligation (rPAL) and sequential window acquisition of all theoretical mass spectra (SWATH-MS), we identified the modified RNA base 3-(3-amino-3-carboxypropyl)uridine (acp3U) as a site of attachment of N-glycans in glycoRNA. rPAL offers sensitivity and robustness as an approach for characterizing direct glycan-RNA linkages occurring in cells, and its flexibility will enable further exploration of glycoRNA biology.


Assuntos
Polissacarídeos , Polissacarídeos/metabolismo , Polissacarídeos/química , Uridina/metabolismo , Uridina/química , Humanos , RNA/metabolismo , RNA/química , Oxirredução
5.
Cell ; 187(1): 62-78.e20, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38096822

RESUMO

The microbiota influences intestinal health and physiology, yet the contributions of commensal protists to the gut environment have been largely overlooked. Here, we discover human- and rodent-associated parabasalid protists, revealing substantial diversity and prevalence in nonindustrialized human populations. Genomic and metabolomic analyses of murine parabasalids from the genus Tritrichomonas revealed species-level differences in excretion of the metabolite succinate, which results in distinct small intestinal immune responses. Metabolic differences between Tritrichomonas species also determine their ecological niche within the microbiota. By manipulating dietary fibers and developing in vitro protist culture, we show that different Tritrichomonas species prefer dietary polysaccharides or mucus glycans. These polysaccharide preferences drive trans-kingdom competition with specific commensal bacteria, which affects intestinal immunity in a diet-dependent manner. Our findings reveal unappreciated diversity in commensal parabasalids, elucidate differences in commensal protist metabolism, and suggest how dietary interventions could regulate their impact on gut health.


Assuntos
Microbioma Gastrointestinal , Parabasalídeos , Polissacarídeos , Animais , Humanos , Camundongos , Fibras na Dieta , Intestino Delgado/metabolismo , Polissacarídeos/metabolismo , Parabasalídeos/metabolismo , Carboidratos da Dieta/metabolismo , Biodiversidade
6.
Cell ; 187(16): 4261-4271.e17, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-38964329

RESUMO

The entry of coronaviruses is initiated by spike recognition of host cellular receptors, involving proteinaceous and/or glycan receptors. Recently, TMPRSS2 was identified as the proteinaceous receptor for HCoV-HKU1 alongside sialoglycan as a glycan receptor. However, the underlying mechanisms for viral entry remain unknown. Here, we investigated the HCoV-HKU1C spike in the inactive, glycan-activated, and functionally anchored states, revealing that sialoglycan binding induces a conformational change of the NTD and promotes the neighboring RBD of the spike to open for TMPRSS2 recognition, exhibiting a synergistic mechanism for the entry of HCoV-HKU1. The RBD of HCoV-HKU1 features an insertion subdomain that recognizes TMPRSS2 through three previously undiscovered interfaces. Furthermore, structural investigation of HCoV-HKU1A in combination with mutagenesis and binding assays confirms a conserved receptor recognition pattern adopted by HCoV-HKU1. These studies advance our understanding of the complex viral-host interactions during entry, laying the groundwork for developing new therapeutics against coronavirus-associated diseases.


Assuntos
Serina Endopeptidases , Glicoproteína da Espícula de Coronavírus , Internalização do Vírus , Humanos , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Polissacarídeos/metabolismo , Polissacarídeos/química , Células HEK293 , Ligação Proteica , Receptores Virais/metabolismo , Receptores Virais/química , Coronavirus/metabolismo , Modelos Moleculares
7.
Cell ; 185(14): 2495-2509.e11, 2022 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-35764090

RESUMO

Plant fibers in byproduct streams produced by non-harsh food processing methods represent biorepositories of diverse, naturally occurring, and physiologically active biomolecules. To demonstrate one approach for their characterization, mass spectrometry of intestinal contents from gnotobiotic mice, plus in vitro studies, revealed liberation of N-methylserotonin from orange fibers by human gut microbiota members including Bacteroides ovatus. Functional genomic analyses of B. ovatus strains grown under permissive and non-permissive N-methylserotonin "mining" conditions revealed polysaccharide utilization loci that target pectins whose expression correlate with strain-specific liberation of this compound. N-methylserotonin, orally administered to germ-free mice, reduced adiposity, altered liver glycogenesis, shortened gut transit time, and changed expression of genes that regulate circadian rhythm in the liver and colon. In human studies, dose-dependent, orange-fiber-specific fecal accumulation of N-methylserotonin positively correlated with levels of microbiome genes encoding enzymes that digest pectic glycans. Identifying this type of microbial mining activity has potential therapeutic implications.


Assuntos
Citrus sinensis , Microbioma Gastrointestinal , Animais , Citrus sinensis/metabolismo , Fibras na Dieta , Microbioma Gastrointestinal/fisiologia , Vida Livre de Germes , Humanos , Camundongos , Pectinas/metabolismo , Polissacarídeos/metabolismo , Serotonina/análogos & derivados
8.
Cell ; 185(20): 3705-3719.e14, 2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36179667

RESUMO

The intestinal microbiota is an important modulator of graft-versus-host disease (GVHD), which often complicates allogeneic hematopoietic stem cell transplantation (allo-HSCT). Broad-spectrum antibiotics such as carbapenems increase the risk for intestinal GVHD, but mechanisms are not well understood. In this study, we found that treatment with meropenem, a commonly used carbapenem, aggravates colonic GVHD in mice via the expansion of Bacteroides thetaiotaomicron (BT). BT has a broad ability to degrade dietary polysaccharides and host mucin glycans. BT in meropenem-treated allogeneic mice demonstrated upregulated expression of enzymes involved in the degradation of mucin glycans. These mice also had thinning of the colonic mucus layer and decreased levels of xylose in colonic luminal contents. Interestingly, oral xylose supplementation significantly prevented thinning of the colonic mucus layer in meropenem-treated mice. Specific nutritional supplementation strategies, including xylose supplementation, may combat antibiotic-mediated microbiome injury to reduce the risk for intestinal GVHD in allo-HSCT patients.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bacteroides , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Meropeném , Camundongos , Mucinas/metabolismo , Muco/metabolismo , Polissacarídeos/metabolismo , Xilose
9.
Cell ; 185(3): 513-529.e21, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35120663

RESUMO

The human gut microbiota resides within a diverse chemical environment challenging our ability to understand the forces shaping this ecosystem. Here, we reveal that fitness of the Bacteroidales, the dominant order of bacteria in the human gut, is an emergent property of glycans and one specific metabolite, butyrate. Distinct sugars serve as strain-variable fitness switches activating context-dependent inhibitory functions of butyrate. Differential fitness effects of butyrate within the Bacteroides are mediated by species-level variation in Acyl-CoA thioesterase activity and nucleotide polymorphisms regulating an Acyl-CoA transferase. Using in vivo multi-omic profiles, we demonstrate Bacteroides fitness in the human gut is associated together, but not independently, with Acyl-CoA transferase expression and butyrate. Our data reveal that each strain of the Bacteroides exists within a unique fitness landscape based on the interaction of chemical components unpredictable by the effect of each part alone mediated by flexibility in the core genome.


Assuntos
Microbioma Gastrointestinal , Metaboloma , Polissacarídeos/metabolismo , Acil Coenzima A/metabolismo , Sequência de Aminoácidos , Aminoácidos de Cadeia Ramificada/metabolismo , Bacteroidetes/efeitos dos fármacos , Bacteroidetes/genética , Bacteroidetes/crescimento & desenvolvimento , Butiratos/química , Butiratos/farmacologia , Coenzima A-Transferases/química , Coenzima A-Transferases/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Variação Genética/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Metaboloma/efeitos dos fármacos , Metaboloma/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Especificidade da Espécie , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Transcrição Gênica/efeitos dos fármacos
10.
Nat Immunol ; 25(9): 1692-1703, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39080486

RESUMO

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut. There is growing evidence in Crohn's disease (CD) of the existence of a preclinical period characterized by immunological changes preceding symptom onset that starts years before diagnosis. Gaining insight into this preclinical phase will allow disease prediction and prevention. Analysis of preclinical serum samples, up to 6 years before IBD diagnosis (from the PREDICTS cohort), revealed the identification of a unique glycosylation signature on circulating antibodies (IgGs) characterized by lower galactosylation levels of the IgG fragment crystallizable (Fc) domain that remained stable until disease diagnosis. This specific IgG2 Fc glycan trait correlated with increased levels of antimicrobial antibodies, specifically anti-Saccharomyces cerevisiae (ASCA), pinpointing a glycome-ASCA hub detected in serum that predates by years the development of CD. Mechanistically, we demonstrated that this agalactosylated glycoform of ASCA IgG, detected in the preclinical phase, elicits a proinflammatory immune pathway through the activation and reprogramming of innate immune cells, such as dendritic cells and natural killer cells, via an FcγR-dependent mechanism, triggering NF-κB and CARD9 signaling and leading to inflammasome activation. This proinflammatory role of ASCA was demonstrated to be dependent on mannose glycan recognition and galactosylation levels in the IgG Fc domain. The pathogenic properties of (anti-mannose) ASCA IgG were validated in vivo. Adoptive transfer of antibodies to mannan (ASCA) to recipient wild-type mice resulted in increased susceptibility to intestinal inflammation that was recovered in recipient FcγR-deficient mice. Here we identify a glycosylation signature in circulating IgGs that precedes CD onset and pinpoint a specific glycome-ASCA pathway as a central player in the initiation of inflammation many years before CD diagnosis. This pathogenic glyco-hub may constitute a promising new serum biomarker for CD prediction and a potential target for disease prevention.


Assuntos
Doença de Crohn , Imunoglobulina G , Manose , Polissacarídeos , Doença de Crohn/imunologia , Doença de Crohn/sangue , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Animais , Humanos , Glicosilação , Manose/metabolismo , Manose/imunologia , Camundongos , Polissacarídeos/imunologia , Polissacarídeos/metabolismo , Feminino , Saccharomyces cerevisiae/imunologia , Masculino , Adulto , Anticorpos Antifúngicos/sangue , Anticorpos Antifúngicos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Biomarcadores/sangue , Pessoa de Meia-Idade , Fragmentos Fc das Imunoglobulinas/imunologia , Glicoproteínas
11.
Nat Rev Mol Cell Biol ; 25(5): 340-358, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38102449

RESUMO

Plant cells build nanofibrillar walls that are central to plant growth, morphogenesis and mechanics. Starting from simple sugars, three groups of polysaccharides, namely, cellulose, hemicelluloses and pectins, with very different physical properties are assembled by the cell to make a strong yet extensible wall. This Review describes the physics of wall growth and its regulation by cellular processes such as cellulose production by cellulose synthase, modulation of wall pH by plasma membrane H+-ATPase, wall loosening by expansin and signalling by plant hormones such as auxin and brassinosteroid. In addition, this Review discusses the nuanced roles, properties and interactions of cellulose, matrix polysaccharides and cell wall proteins and describes how wall stress and wall loosening cooperatively result in cell wall growth.


Assuntos
Parede Celular , Celulose , Células Vegetais , Parede Celular/metabolismo , Celulose/metabolismo , Células Vegetais/metabolismo , Proteínas de Plantas/metabolismo , Desenvolvimento Vegetal/fisiologia , Plantas/metabolismo , Polissacarídeos/metabolismo , Glucosiltransferases/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Transdução de Sinais
12.
Cell ; 184(12): 3109-3124.e22, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34004145

RESUMO

Glycans modify lipids and proteins to mediate inter- and intramolecular interactions across all domains of life. RNA is not thought to be a major target of glycosylation. Here, we challenge this view with evidence that mammals use RNA as a third scaffold for glycosylation. Using a battery of chemical and biochemical approaches, we found that conserved small noncoding RNAs bear sialylated glycans. These "glycoRNAs" were present in multiple cell types and mammalian species, in cultured cells, and in vivo. GlycoRNA assembly depends on canonical N-glycan biosynthetic machinery and results in structures enriched in sialic acid and fucose. Analysis of living cells revealed that the majority of glycoRNAs were present on the cell surface and can interact with anti-dsRNA antibodies and members of the Siglec receptor family. Collectively, these findings suggest the existence of a direct interface between RNA biology and glycobiology, and an expanded role for RNA in extracellular biology.


Assuntos
Membrana Celular/metabolismo , Polissacarídeos/metabolismo , RNA/metabolismo , Animais , Anticorpos/metabolismo , Sequência de Bases , Vias Biossintéticas , Linhagem Celular , Sobrevivência Celular , Humanos , Espectrometria de Massas , Ácido N-Acetilneuramínico/metabolismo , Poliadenilação , Polissacarídeos/química , RNA/química , RNA/genética , RNA não Traduzido/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Coloração e Rotulagem
13.
Cell ; 184(24): 5869-5885.e25, 2021 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-34758294

RESUMO

RTN4-binding proteins were widely studied as "NoGo" receptors, but their physiological interactors and roles remain elusive. Similarly, BAI adhesion-GPCRs were associated with numerous activities, but their ligands and functions remain unclear. Using unbiased approaches, we observed an unexpected convergence: RTN4 receptors are high-affinity ligands for BAI adhesion-GPCRs. A single thrombospondin type 1-repeat (TSR) domain of BAIs binds to the leucine-rich repeat domain of all three RTN4-receptor isoforms with nanomolar affinity. In the 1.65 Å crystal structure of the BAI1/RTN4-receptor complex, C-mannosylation of tryptophan and O-fucosylation of threonine in the BAI TSR-domains creates a RTN4-receptor/BAI interface shaped by unusual glycoconjugates that enables high-affinity interactions. In human neurons, RTN4 receptors regulate dendritic arborization, axonal elongation, and synapse formation by differential binding to glial versus neuronal BAIs, thereby controlling neural network activity. Thus, BAI binding to RTN4/NoGo receptors represents a receptor-ligand axis that, enabled by rare post-translational modifications, controls development of synaptic circuits.


Assuntos
Inibidores da Angiogênese/metabolismo , Encéfalo/metabolismo , Neurogênese , Neurônios/metabolismo , Proteínas Nogo/metabolismo , Receptores Nogo/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adipocinas/metabolismo , Sequência de Aminoácidos , Animais , Axônios/metabolismo , Adesão Celular , Moléculas de Adesão Celular Neuronais/metabolismo , Complemento C1q/metabolismo , Dendritos/metabolismo , Glicosilação , Células HEK293 , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Ligantes , Camundongos Endogâmicos C57BL , Rede Nervosa/metabolismo , Polissacarídeos/metabolismo , Ligação Proteica , Domínios Proteicos , Deleção de Sequência , Sinapses/metabolismo , Transmissão Sináptica/fisiologia
14.
Annu Rev Cell Dev Biol ; 37: 257-283, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34613816

RESUMO

Morphological transitions are typically attributed to the actions of proteins and lipids. Largely overlooked in membrane shape regulation is the glycocalyx, a pericellular membrane coat that resides on all cells in the human body. Comprised of complex sugar polymers known as glycans as well as glycosylated lipids and proteins, the glycocalyx is ideally positioned to impart forces on the plasma membrane. Large, unstructured polysaccharides and glycoproteins in the glycocalyx can generate crowding pressures strong enough to induce membrane curvature. Stress may also originate from glycan chains that convey curvature preference on asymmetrically distributed lipids, which are exploited by binding factors and infectious agents to induce morphological changes. Through such forces, the glycocalyx can have profound effects on the biogenesis of functional cell surface structures as well as the secretion of extracellular vesicles. In this review, we discuss recent evidence and examples of these mechanisms in normal health and disease.


Assuntos
Glicocálix , Membrana Celular/metabolismo , Glicocálix/química , Glicocálix/metabolismo , Glicoproteínas , Humanos , Polissacarídeos/análise , Polissacarídeos/química , Polissacarídeos/metabolismo
15.
Cell ; 178(1): 202-215.e14, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31204102

RESUMO

Despite the worldwide success of vaccination, newborns remain vulnerable to infections. While neonatal vaccination has been hampered by maternal antibody-mediated dampening of immune responses, enhanced regulatory and tolerogenic mechanisms, and immune system immaturity, maternal pre-natal immunization aims to boost neonatal immunity via antibody transfer to the fetus. However, emerging data suggest that antibodies are not transferred equally across the placenta. To understand this, we used systems serology to define Fc features associated with antibody transfer. The Fc-profile of neonatal and maternal antibodies differed, skewed toward natural killer (NK) cell-activating antibodies. This selective transfer was linked to digalactosylated Fc-glycans that selectively bind FcRn and FCGR3A, resulting in transfer of antibodies able to efficiently leverage innate immune cells present at birth. Given emerging data that vaccination may direct antibody glycosylation, our study provides insights for the development of next-generation maternal vaccines designed to elicit antibodies that will most effectively aid neonates.


Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunoglobulina G/metabolismo , Placenta/metabolismo , Polissacarídeos/metabolismo , Receptores Fc/imunologia , Receptores Fc/metabolismo , Adolescente , Adulto , Bélgica , Degranulação Celular , Estudos de Coortes , Feminino , Glicosilação , Humanos , Recém-Nascido , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Masculino , Gravidez , Receptores de IgG/metabolismo , Células THP-1 , Estados Unidos , Vacinação , Adulto Jovem
16.
Cell ; 179(1): 59-73.e13, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31539500

RESUMO

Development of microbiota-directed foods (MDFs) that selectively increase the abundance of beneficial human gut microbes, and their expressed functions, requires knowledge of both the bioactive components of MDFs and the mechanisms underlying microbe-microbe interactions. Here, gnotobiotic mice were colonized with a defined consortium of human-gut-derived bacterial strains and fed different combinations of 34 food-grade fibers added to a representative low-fiber diet consumed in the United States. Bioactive carbohydrates in fiber preparations targeting particular Bacteroides species were identified using community-wide quantitative proteomic analyses of bacterial gene expression coupled with forward genetic screens. Deliberate manipulation of community membership combined with administration of retrievable artificial food particles, consisting of paramagnetic microscopic beads coated with dietary polysaccharides, disclosed the contributions of targeted species to fiber degradation. Our approach, including the use of bead-based biosensors, defines nutrient-harvesting strategies that underlie, as well as alleviate, competition between Bacteroides and control the selectivity of MDF components.


Assuntos
Bacteroides/genética , Fibras na Dieta/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Vida Livre de Germes/fisiologia , Interações Microbianas/efeitos dos fármacos , Polissacarídeos/farmacologia , Proteômica/métodos , Animais , Dieta/métodos , Fibras na Dieta/metabolismo , Fezes/microbiologia , Microbioma Gastrointestinal/fisiologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polissacarídeos/metabolismo
17.
Nat Rev Mol Cell Biol ; 21(12): 729-749, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33087899

RESUMO

Glycosylation is the most abundant and diverse form of post-translational modification of proteins that is common to all eukaryotic cells. Enzymatic glycosylation of proteins involves a complex metabolic network and different types of glycosylation pathways that orchestrate enormous amplification of the proteome in producing diversity of proteoforms and its biological functions. The tremendous structural diversity of glycans attached to proteins poses analytical challenges that limit exploration of specific functions of glycosylation. Major advances in quantitative transcriptomics, proteomics and nuclease-based gene editing are now opening new global ways to explore protein glycosylation through analysing and targeting enzymes involved in glycosylation processes. In silico models predicting cellular glycosylation capacities and glycosylation outcomes are emerging, and refined maps of the glycosylation pathways facilitate genetic approaches to address functions of the vast glycoproteome. These approaches apply commonly available cell biology tools, and we predict that use of (single-cell) transcriptomics, genetic screens, genetic engineering of cellular glycosylation capacities and custom design of glycoprotein therapeutics are advancements that will ignite wider integration of glycosylation in general cell biology.


Assuntos
Glicoproteínas/metabolismo , Polissacarídeos/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Proteoma/metabolismo , Metabolismo dos Carboidratos/fisiologia , Glicosilação , Humanos , Redes e Vias Metabólicas/fisiologia , Polissacarídeos/química
18.
Cell ; 171(1): 258-258.e1, 2017 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-28938118

RESUMO

Post-translational modification of proteins with carbohydrates shapes their localization and function. This SnapShot presents the core pathways from different organisms that install these complex and highly variable structures.


Assuntos
Eucariotos/metabolismo , Glicosilação , Animais , Evolução Biológica , Eucariotos/classificação , Eucariotos/citologia , Humanos , Polissacarídeos/metabolismo
19.
Cell ; 169(7): 1249-1262.e13, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28622510

RESUMO

Homeostasis of the gut microbiota critically influences host health and aging. Developing genetically engineered probiotics holds great promise as a new therapeutic paradigm to promote healthy aging. Here, through screening 3,983 Escherichia coli mutants, we discovered that 29 bacterial genes, when deleted, increase longevity in the host Caenorhabditis elegans. A dozen of these bacterial mutants also protect the host from age-related progression of tumor growth and amyloid-beta accumulation. Mechanistically, we discovered that five bacterial mutants promote longevity through increased secretion of the polysaccharide colanic acid (CA), which regulates mitochondrial dynamics and unfolded protein response (UPRmt) in the host. Purified CA polymers are sufficient to promote longevity via ATFS-1, the host UPRmt-responsive transcription factor. Furthermore, the mitochondrial changes and longevity effects induced by CA are conserved across different species. Together, our results identified molecular targets for developing pro-longevity microbes and a bacterial metabolite acting on host mitochondria to promote longevity.


Assuntos
Caenorhabditis elegans/microbiologia , Escherichia coli/genética , Longevidade , Envelhecimento/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Carga Bacteriana , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Escherichia coli/metabolismo , Deleção de Genes , Estudo de Associação Genômica Ampla , Dinâmica Mitocondrial , Modelos Animais , Polissacarídeos/metabolismo , Fatores de Transcrição/metabolismo , Resposta a Proteínas não Dobradas
20.
Mol Cell ; 84(19): 3576-3577, 2024 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-39366345

RESUMO

In a recent publication in Cell, Xie et al.1 report a sensitive and scalable method for the detection and characterization of native glycoRNAs and identify acp3U, an abundant modified nucleoside discovered 50 years ago in tRNAPhe, as one of the primary attachment sites for N-glycans.


Assuntos
Polissacarídeos , Polissacarídeos/metabolismo , Polissacarídeos/química , Humanos , RNA Nucleolar Pequeno/metabolismo , RNA Nucleolar Pequeno/genética , RNA Nucleolar Pequeno/química , Nucleosídeos/química , Nucleosídeos/metabolismo , Aminoácidos/química , Aminoácidos/metabolismo
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