<scp>GILT</scp> expression in <scp>B</scp> cells diminishes cathepsin <scp>S</scp> steady‐state protein expression and activity

Phipps-Yonas, Hannah; Semik, Vikki; Hastings, Karen Taraszka

doi:10.1002/eji.201242379

Cited by 24 publications

(17 citation statements)

References 48 publications

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“…Rather as shown here, c-MYC overexpression influences cellular expression of DM, DO and GILT, critical components which modulate the efficiency of class II Ag presentation. GILT reduces disulfide bonds in Ags which allows proteins to be unfolded and further processed by acidic proteases (56, 70, 71, 87). The importance of GILT for the class II pathway has been demonstrated in GILT −/− mice which are defective in their ability to process Ag, although they express normal levels of class II (47, 88, 89).…”

Section: Discussionmentioning

confidence: 99%

Elevation of c-MYC Disrupts HLA Class II–Mediated Immune Recognition of Human B Cell Tumors

God

Cameron

Figueroa

et al. 2015

The Journal of Immunology

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Elevated levels of the transcription factor c-myc are strongly associated with various cancers, and in particular B-cell lymphomas. While many of c-MYC’s functions have been elucidated, its effect on the presentation of antigen (Ag) through the HLA class II pathway has not previously been reported. This is an issue of considerable importance, given the low immunogenicity of many c-MYC-positive tumors. We report here that increased c-MYC expression has a negative effect on the ability of B-cell lymphomas to functionally present Ags/peptides to CD4+ T cells. This defect was associated with alterations in the expression of distinct co-factors as well as interactions of antigenic peptides with class II molecules required for the presentation of class II-peptide complexes and T cell engagement. Using early passage Burkitt’s lymphoma (BL) tumors and transformed cells, we show that compared to B-lymphoblasts, BL cells express decreased levels of the class II editor HLA-DM, lysosomal thiol-reductase GILT, and a 47kDa enolase-like protein. Functional Ag presentation was partially restored in BL cells treated with a c-MYC inhibitor, demonstrating the impact of this oncogene on Ag recognition. This restoration of HLA class II-mediated Ag presentation in early passage BL tumors/cells was linked to enhanced HLA-DM expression and a concurrent decrease in HLA-DO in BL cells. Taken together, these results reveal c-MYC exerts suppressive effects at several critical checkpoints in Ag presentation which contribute to the immunoevasive properties of BL tumors.

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Section: Discussionmentioning

confidence: 99%

Elevation of c-MYC Disrupts HLA Class II–Mediated Immune Recognition of Human B Cell Tumors

God

Cameron

Figueroa

et al. 2015

The Journal of Immunology

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“…On one hand, we have shown that GILT’s reductase activity facilitates the degradation of cathepsin S (Phipps-Yonas et al, 2013b). On the other hand, GILT maintains the proteolytic activity of cathepsin S (Balce et al, 2014).…”

Section: Gilt In Antigen Presentationmentioning

confidence: 99%

Diverse cellular and organismal functions of the lysosomal thiol reductase GILT

Rausch

Hastings

2015

Molecular Immunology

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Gamma-interferon-inducible lysosomal thiol reductase (GILT) is the only enzyme known to catalyze disulfide bond reduction in the endocytic pathway. GILT facilitates the presentation of a subset of epitopes from disulfide bond-containing antigens. Enhanced presentation of MHC class II-restricted epitopes alters central tolerance and modulates CD4+ T cell-mediated autoimmunity. Improved cross-presentation of viral epitopes results in improved cross-priming of viral-specific CD8+ T cells. GILT regulates the cellular redox state. In GILT−/− cells, there is a shift from the reduced to the oxidized form of glutathione, resulting in mitochondrial autophagy, decreased superoxide dismutase 2, and elevated superoxide levels. GILT expression diminishes cellular activation, including decreased phosphorylated ERK1/2, and decreases cellular proliferation. GILT enhances the activity of bacterial hemolysins, such as listeriolysin O, and increases bacterial replication and infection. GILT expression in cancer cells is associated with improved patient survival. These diverse roles of GILT are discussed.

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“…Upon translation, GILT is sorted by mannose 6-phosphate receptor pathway to endocytic compartments and finally transported into the lysosome that provides optimal low pH for its thiol reductase activity [16,17]. As the only thiol reductase in endolysosomes and phagosomes, GILT contributes to the degradation of lysosomal protease cathepsin, maintenance of cellular normal redox state and prohibition of aberrant autophagy [18][19][20][21]. GILT utilizes two cysteine residues in the CXXC reductase motif to reduce the disulphide bond of endocytosed antigens to facilitate antigen processing and presentation by MHC II and MHC-I [16,17,[22][23][24].…”

Section: Introductionmentioning

confidence: 99%

GILT restricts the cellular entry mediated by the envelope glycoproteins of SARS-CoV, Ebola virus and Lassa fever virus

Chen

Hou

Jiang

et al. 2019

Emerging Microbes & Infections

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Interferons (IFNs) control viral infections by inducing expression of IFN-stimulated genes (ISGs) that restrict distinct steps of viral replication. We report herein that gamma-interferon-inducible lysosomal thiol reductase (GILT), a lysosome-associated ISG, restricts the infectious entry of selected enveloped RNA viruses. Specifically, we demonstrated that GILT was constitutively expressed in lung epithelial cells and fibroblasts and its expression could be further induced by type II interferon. While overexpression of GILT inhibited the entry mediated by envelope glycoproteins of SARS coronavirus (SARS-CoV), Ebola virus (EBOV) and Lassa fever virus (LASV), depletion of GILT enhanced the entry mediated by these viral envelope glycoproteins. Furthermore, mutations that impaired the thiol reductase activity or disrupted the N-linked glycosylation, a posttranslational modification essential for its lysosomal localization, largely compromised GILT restriction of viral entry. We also found that the induction of GILT expression reduced the level and activity of cathepsin L, which is required for the entry of these RNA viruses in lysosomes. Our data indicate that GILT is a novel antiviral ISG that specifically inhibits the entry of selected enveloped RNA viruses in lysosomes via disruption of cathepsin L metabolism and function and may play a role in immune control and pathogenesis of these viruses.

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GILT expression in B cells diminishes cathepsin S steady‐state protein expression and activity

Cited by 24 publications

References 48 publications

Elevation of c-MYC Disrupts HLA Class II–Mediated Immune Recognition of Human B Cell Tumors

Elevation of c-MYC Disrupts HLA Class II–Mediated Immune Recognition of Human B Cell Tumors

Diverse cellular and organismal functions of the lysosomal thiol reductase GILT

GILT restricts the cellular entry mediated by the envelope glycoproteins of SARS-CoV, Ebola virus and Lassa fever virus

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