Exosomes

Annual Review of Biochemistry, Journal Year: 2019, Volume and Issue: 88(1), P. 487 - 514

Published: June 20, 2019

Exosomes are small, single-membrane, secreted organelles of ∼30 to ∼200 nm in diameter that have the same topology as cell and enriched selected proteins, lipids, nucleic acids, glycoconjugates. contain an array membrane-associated, high-order oligomeric protein complexes, display pronounced molecular heterogeneity, created by budding at both plasma endosome membranes. Exosome biogenesis is a mechanism quality control, once released, exosomes activities diverse remodeling extracellular matrix transmitting signals molecules other cells. This pathway intercellular vesicle traffic plays important roles many aspects human health disease, including development, immunity, tissue homeostasis, cancer, neurodegenerative diseases. In addition, viruses co-opt exosome pathways for assembling infectious particles establishing host permissiveness. On basis these properties, being developed therapeutic agents multiple disease models.

Language: Английский

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Glycosylation in health and disease

Nature Reviews Nephrology, Journal Year: 2019, Volume and Issue: 15(6), P. 346 - 366

Published: March 11, 2019

Language: Английский

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Small RNAs are modified with N-glycans and displayed on the surface of living cells

Cell, Journal Year: 2021, Volume and Issue: 184(12), P. 3109 - 3124.e22

Published: May 17, 2021

Language: Английский

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Siglecs as Immune Cell Checkpoints in Disease

Annual Review of Immunology, Journal Year: 2020, Volume and Issue: 38(1), P. 365 - 395

Published: Jan. 27, 2020

Sialic acid–binding immunoglobulin-type lectins (Siglecs) are expressed on the majority of white blood cells immune system and play critical roles in cell signaling. Through recognition sialic acid–containing glycans as ligands, they help distinguish between self nonself. Because their restricted type expression checkpoints responses human diseases such cancer, asthma, allergy, neurodegeneration, autoimmune have gained attention targets for therapeutic interventions. In this review we describe Siglec family, its regulation signaling, current efforts to define disease processes, approaches target Siglecs treatment disease.

Language: Английский

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The mucin-selective protease StcE enables molecular and functional analysis of human cancer-associated mucins

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(15), P. 7278 - 7287

Published: March 25, 2019

Mucin domains are densely O-glycosylated modular protein that found in a wide variety of cell surface and secreted proteins. Mucin-domain glycoproteins known to be key players host human diseases, especially cancer, wherein mucin expression glycosylation patterns altered. biology has been difficult study at the molecular level, part, because methods manipulate structurally characterize lacking. Here, we demonstrate protease C1 esterase inhibitor (StcE), bacterial from Escherichia coli, cleaves by recognizing discrete peptide- glycan-based motif. We exploited StcE's unique properties improve sequence coverage, glycosite mapping, glycoform analysis recombinant mucins mass spectrometry. also StcE digests cancer-associated cultured cells ascites fluid derived patients with ovarian cancer. Finally, using StcE, discovered sialic acid-binding Ig-type lectin-7 (Siglec-7), glycoimmune checkpoint receptor, selectively binds sialomucins as biological ligands, whereas related receptor Siglec-9 does not. Mucin-selective proteolysis, exemplified is therefore powerful tool for domain structure function.

Language: Английский

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Sialic Acid Blockade Suppresses Tumor Growth by Enhancing T-cell–Mediated Tumor Immunity

Cancer Research, Journal Year: 2018, Volume and Issue: 78(13), P. 3574 - 3588

Published: April 27, 2018

Abstract Sialic acid sugars on the surface of cancer cells have emerged as potent immune modulators that contribute to immunosuppressive microenvironment and tumor evasion. However, mechanisms by which these modulate antitumor immunity well therapeutic strategies directed against them are limited. Here we report intratumoral injections with a sialic mimetic Ac53FaxNeu5Ac block expression in vivo suppress growth multiple models. blockade had major impact cell composition tumor, enhancing tumor-infiltrating natural killer CD8+ T-cell numbers while reducing regulatory myeloid numbers. enhanced cytotoxic T-cell–mediated killing part facilitating antigen-specific T-cell–tumor clustering. also synergized adoptive transfer tumor-specific T CpG adjuvant therapy increasing dendritic activation subsequent responses. Collectively, data emphasize crucial role acids evasion provide proof concept creates an immune-permissive for immunity, either single treatment or combination other immune-based intervention strategies. Significance: function important limit immunity. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3574/F1.large.jpg. Cancer Res; 78(13); 3574–88. ©2018 AACR.

Language: Английский

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Altered Cell Adhesion and Glycosylation Promote Cancer Immune Suppression and Metastasis

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: Sept. 6, 2019

Cell-cell interactions and cell adhesion are key mediators of cancer progression facilitate hallmarks including immune evasion metastatic dissemination. Many molecules within the tumor microenvironment changed significant alterations glycosylation observed. These changes in alter ability cells to interact with other extracellular matrix proteins. Three families cell-cell interaction selectins, Siglecs, integrins have been associated many pre-clinical studies, yet inhibition as a therapeutic target is just beginning be explored. We review how mediated by glycan-binding receptors selectins Siglec support progression. The discussion focuses on mechanisms during metastasis that can therapeutically targeted blocking these interactions.

Language: Английский

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Hypersialylation in Cancer: Modulation of Inflammation and Therapeutic Opportunities

Cancers, Journal Year: 2018, Volume and Issue: 10(6), P. 207 - 207

Published: June 18, 2018

Cell surface glycosylation is dynamic and often changes in response to cellular differentiation under physiological or pathophysiological conditions. Altered on cancers cells gaining attention due its wide-spread occurrence across a variety of cancer types recent studies that have documented functional roles for aberrant driving progression at various stages. One change can correlate with stage disease prognosis hypersialylation. Increased levels sialic acid are pervasive growing body evidence demonstrates how hypersialylation advantageous cells, particularly from the perspective modulating immune cell responses. Sialic acid-binding receptors, such as Siglecs Selectins, well-positioned be exploited by Evidence also mounting modulate key tumor microenvironment, those responsible maintaining appropriate inflammatory environment. From these come new innovative ways block effects directly reducing blocking interactions between Selectins. Here we review works examining become hypersialylated, benefits tumors, proposed therapies abrogate cancer.

Language: Английский

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Glycosylation in cancer: Selected roles in tumour progression, immune modulation and metastasis

Cellular Immunology, Journal Year: 2018, Volume and Issue: 333, P. 46 - 57

Published: March 20, 2018

Language: Английский

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Targeting cancer glycosylation repolarizes tumor-associated macrophages allowing effective immune checkpoint blockade

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 14(669)

Published: Nov. 2, 2022

Immune checkpoint blockade (ICB) has substantially improved the prognosis of patients with cancer, but majority experiences limited benefit, supporting need for new therapeutic approaches. Up-regulation sialic acid–containing glycans, termed hypersialylation, is a common feature cancer-associated glycosylation, driving disease progression and immune escape through engagement Siglec receptors on tumor-infiltrating cells. Here, we show that tumor sialylation correlates distinct states reduced survival in human cancers. The targeted removal ligands microenvironment, using an antibody-sialidase conjugate, enhanced antitumor immunity halted several murine models. Using single-cell RNA sequencing, revealed desialylation repolarized tumor-associated macrophages (TAMs). We also identified Siglec-E as main receptor hypersialylation TAMs. Last, found genetic desialylation, well loss Siglec-E, efficacy ICB. Thus, represents immunotherapeutic approach to reshape macrophage phenotypes augment adaptive response.

Language: Английский

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