Endo-lysosomal proteases in antigen presentation

Kasteren, Sander I. van; Overkleeft, Herman S.

doi:10.1016/j.cbpa.2014.08.011

Cited by 39 publications

(34 citation statements)

References 70 publications

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“…As an explanation, it was proposed that B cells take up exogenous CatG (e.g., produced in myeloid APCs) (53), although this is not a satisfactory explanation for the high CatG activity observed in the LCV-transformed B cell lines. Because CatG is transcribed as proform, the activity could be due to variations in activation and deactivation of the bioactive enzyme (54). We also observed inhibition of rhMOG degradation by the cysteine protease inhibitor E64.…”

Section: Prolongation Of the Half-life Of The Ctl Epitopementioning

confidence: 59%

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

Jagessar

Holtman

Hofman

et al. 2016

The Journal of Immunology

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EBV is the major infectious environmental risk factor for multiple sclerosis (MS), but the underlying mechanisms remain obscure. Patient studies do not allow manipulation in vivo. We used the experimental autoimmune encephalomyelitis (EAE) models in the common marmoset and rhesus monkey to model the association of EBV and MS. We report that B cells infected with EBV-related lymphocryptovirus (LCV) are requisite APCs for MHC-E–restricted autoaggressive effector memory CTLs specific for the immunodominant epitope 40-48 of myelin oligodendrocyte glycoprotein (MOG). These T cells drive the EAE pathogenesis to irreversible neurologic deficit. The aim of this study was to determine why LCV infection is important for this pathogenic role of B cells. Transcriptome comparison of LCV-infected B cells and CD20+ spleen cells from rhesus monkeys shows increased expression of genes encoding elements of the Ag cross-presentation machinery (i.e., of proteasome maturation protein and immunoproteasome subunits) and enhanced expression of MHC-E and of costimulatory molecules (CD70 and CD80, but not CD86). It was also shown that altered expression of endolysosomal proteases (cathepsins) mitigates the fast endolysosomal degradation of the MOG40–48 core epitope. Finally, LCV infection also induced expression of LC3-II+ cytosolic structures resembling autophagosomes, which seem to form an intracellular compartment where the MOG40–48 epitope is protected against proteolytic degradation by the endolysosomal serine protease cathepsin G. In conclusion, LCV infection induces a variety of changes in B cells that underlies the conversion of destructive processing of the immunodominant MOG40–48 epitope into productive processing and cross-presentation to strongly autoaggressive CTLs.

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Section: Prolongation Of the Half-life Of The Ctl Epitopementioning

confidence: 59%

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

Jagessar

Holtman

Hofman

et al. 2016

The Journal of Immunology

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“…Key enzymes implicated in epitope generation for MHCII presentation include lysosomal proteases that can be classified based on their catalytic mechanism into four major families (Table 1): (1) the cysteine cathepsins with a papain-fold (B, C, F, H, K, L, O, S, V, W, and X); (2) the aspartyl cathepsins D and E; (3) the serine cathepsins A and G, and (4) single member family of asparagine endopeptidase (AEP), a cysteine protease grouped with the caspases (82). In addition, gamma-interferon-inducible lysosomal thiol reductase (GILT) cleaves protein disulfide bonds (83).…”

Section: Generation Of the Mhcii/peptide Repertoire: Proteases And Rementioning

confidence: 99%

“…Studies of B cells and DCs from animals deficient in Cat S showed accumulation of surface MHCII with the 10 kDa Ii fragment (100), and reduced antigen presentation. In mice, in the absence of Cat S and L, Cat F in macrophages can generate CLIP, indicating cathepsin redundancy (82). …”

Section: Generation Of the Mhcii/peptide Repertoire: Proteases And Rementioning

confidence: 99%

The Other Function: Class II-Restricted Antigen Presentation by B Cells

et al. 2017

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Mature B lymphocytes (B cells) recognize antigens using their B cell receptor (BCR) and are activated to become antibody-producing cells. In addition, and integral to the development of a high-affinity antibodies, B cells utilize the specialized major histocompatibility complex class II (MHCII) antigen presentation pathway to process BCR-bound and internalized protein antigens and present selected peptides in complex with MHCII to CD4+ T cells. This interaction influences the fate of both types of lymphocytes and shapes immune outcomes. Specific, effective, and optimally timed antigen presentation by B cells requires well-controlled intracellular machinery, often regulated by the combined effects of several molecular events. Here, we delineate and summarize these events in four steps along the antigen presentation pathway: (1) antigen capture and uptake by B cells; (2) intersection of internalized antigen/BCRs complexes with MHCII in peptide-loading compartments; (3) generation and regulation of MHCII/peptide complexes; and (4) exocytic transport for presentation of MHCII/peptide complexes at the surface of B cells. Finally, we discuss modulation of the MHCII presentation pathway across B cell development and maturation to effector cells, with an emphasis on the shaping of the MHCII/peptide repertoire by two key antigen presentation regulators in B cells: HLA-DM and HLA-DO.

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“…The exact mechanisms and pathways by which endolysosmal proteolysis impacts antigen presentation, signal transduction and the interplay between the different proteases and other enzymes remain only partly understood. 31 We believe that the chemical tools presented here will help to answer some of these remaining questions.…”

Section: Introductionmentioning

confidence: 95%

Design of a Highly Selective Quenched Activity-Based Probe and Its Application in Dual Color Imaging Studies of Cathepsin S Activity Localization

Bender¹,

Ofori²,

Linden³

et al. 2015

J. Am. Chem. Soc.

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The cysteine cathepsins are a group of 11 proteases whose function was originally believed to be the degradation of endocytosed material with a high degree of redundancy. However, it has become clear that these enzymes are also important regulators of both health and disease. Thus, selective tools that can discriminate between members of this highly related class of enzymes will be critical to further delineate the unique biological functions of individual cathepsins. Here we present the design and synthesis of a near-infrared quenched activity-based probe (qABP) that selectively targets cathepsin S which is highly expressed in immune cells. Importantly, this high degree of selectivity is retained both in vitro and in vivo. In combination with a new green-fluorescent pan-reactive cysteine cathepsin qABP we performed dual color labeling studies in bone marrow derived immune cells and identified vesicles containing exclusively cathepsin S activity. This observation demonstrates the value of our complimentary cathepsin probes and provides evidence for the existence of specific localization of cathepsin S activity in dendritic cells.

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Endo-lysosomal proteases in antigen presentation

Cited by 39 publications

References 70 publications

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

The Other Function: Class II-Restricted Antigen Presentation by B Cells

Design of a Highly Selective Quenched Activity-Based Probe and Its Application in Dual Color Imaging Studies of Cathepsin S Activity Localization

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