Role for Cathepsin F in Invariant Chain Processing and Major Histocompatibility Complex Class II Peptide Loading by Macrophages

Shi, Guo‐Ping; Bryant, Rebecca A.R.; Riese, Richard J.; Verhelst, Steven H. L.; Driessen, Christoph; Li, Zhenqiang; Brὂmme, Dieter; Ploegh, Hidde L.; Chapman, Harold A.

doi:10.1084/jem.191.7.1177

Cited by 220 publications

(169 citation statements)

References 41 publications

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“…Processing of Ii appears to be based on redundant protease activities (Costantino et al 2008) with the exception of the cleavage of the p10 intermediate degradation product into CLIP. This requires cathepsin S (Riese et al 1996;Driessen et al 1999;Nakagawa et al 1999;Shi et al 1999) or cathepsins L and F (Nakagawa et al 1998;Shi et al 2000), depending on the cell type. Degradation of the remaining transmembrane fragment requires the intramembrane endopeptidase SPPL2A (Beisner et al 2013;Bergmann et al 2013;Schneppenheim et al 2013).…”

Section: Biosynthesis Of Mhciimentioning

confidence: 99%

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Broeke

Wubbolts

Stoorvogel

2013

Cold Spring Harbor Perspectives in Biology

142

102

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For the initiation of adaptive immune responses, dendritic cells present antigenic peptides in association with major histocompatibility complex class II (MHCII) to naïve CD4 þ T lymphocytes. In this review, we discuss how antigen presentation is regulated through intracellular processing and trafficking of MHCII. Newly synthesized MHCII is chaperoned by the invariant chain to endosomes, where peptides from endocytosed pathogens can bind. In nonactivated dendritic cells, peptide-loaded MHCII is ubiquitinated and consequently sorted by the ESCRT machinery to intraluminal vesicles of multivesicular bodies, ultimately leading to lysosomal degradation. Ubiquitination of newly synthesized MHCII is blocked when dendritic cells are activated, now allowing its transfer to the cell surface. This mode of regulation for MHCII is a prime example of how molecular processing and sorting at multivesicular bodies can determine the expression of signaling receptors at the plasma membrane.

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Section: Biosynthesis Of Mhciimentioning

confidence: 99%

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Broeke

Wubbolts

Stoorvogel

2013

Cold Spring Harbor Perspectives in Biology

142

102

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“…In Cat L-deficient mice, this cleavage is impaired in cortical thymic epithelial cells (11). Cat F can compensate for loss of Cat L and Cat S in macrophages (12). The initial proteolytic steps in the degradation of Ii are less well understood.…”

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confidence: 99%

Asparagine Endopeptidase Is Not Essential for Class II MHC Antigen Presentation but Is Required for Processing of Cathepsin L in Mice

Maehr

Hang²,

Mintern³

et al. 2005

The Journal of Immunology

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104

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Class II MHC molecules survey the endocytic compartments of APCs and present antigenic peptides to CD4 T cells. In this context, lysosomal proteases are essential not only for the generation of antigenic peptides but also for proteolysis of the invariant chain to allow the maturation of class II MHC molecules. Recent studies with protease inhibitors have implicated the asparagine endopeptidase (AEP) in class II MHC-restricted Ag presentation. We now report that AEP-deficient mice show no differences in processing of the invariant chain or maturation of class II MHC products compared with wild-type mice. In the absence of AEP, presentation to primary T cells of OVA and myelin oligodendrocyte glycoprotein, two Ags that contain asparagine residues within or in proximity to the relevant epitopes was unimpaired. Cathepsin (Cat) L, a lysosomal cysteine protease essential for the development to CD4 and NK T cells, fails to be processed into its mature two-chain form in AEP-deficient cells. Despite this, the numbers of CD4 and NK T cells are normal, showing that the single-chain form of Cat L is sufficient for its function in vivo. We conclude that AEP is essential for processing of Cat L but not for class II MHC-restricted Ag presentation.

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“…Cathepsin S expression has predominantly been associated with cells of monocyte-macrophage lineage. Functions ascribed to CatS include degradation of the MHC class II chaperone II before peptide loading in the endosomal compartment 16,17,18 and processing of the amyloid precursor protein. 19 Secreted macrophage-derived cysteine proteinases (including CatS) are implicated in ECM remodeling in both pathological 20 and physiological conditions.…”

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confidence: 99%

The Clinical Significance of Cathepsin S Expression in Human Astrocytomas

Flannery¹,

Gibson²,

Mirakhur³

et al. 2003

The American Journal of Pathology

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Early local invasion by astrocytoma cells results in tumor recurrence even after apparent total surgical resection, leading to the poor prognosis associated with malignant astrocytomas. Proteolytic enzymes have been implicated in facilitating tumor cell invasion and the current study was designed to characterize the expression of the cysteine proteinase cathepsin S (CatS) in astrocytomas and examine its potential role in invasion. Immunohistochemical analysis of biopsies demonstrated that CatS was expressed in astrocytoma cells but absent from normal astrocytes, oligodendrocytes, neurones and endothelial cells. Microglial cells and macrophages were also positive. Assays of specific activity in 59 astrocytoma biopsies confirmed CatS expression and in addition demonstrated that the highest levels of activity were expressed in grade IV tumors. CatS activity was also present in astrocytoma cells in vitro and the extracellular levels of activity were highest in cultures derived from grade IV tumors. In vitro invasion assays were carried out using the U251MG cell line and the invasion rate was reduced by up to 61% in the presence of the selective CatS inhibitor 4-Morpholineurea-LeuHomoPhe-vinylsulphone. We conclude that CatS expression is up-regulated in astrocytoma cells and provide evidence for a potential role for CatS in invasion. Astrocytomas are the commonest primary brain tumors and within this group the malignant grade III and IV tumors predominate (anaplastic astrocytomas and glioblastomas). Despite their non-metastatic nature, prognosis is poor because tumor infiltration of surrounding brain leads to recurrence even after apparently radical surgery. Multiple stereotactic biopsies of astrocytomas have demonstrated isolated tumor cells at considerable distances from the main tumor mass, 1 and recent investigations 2 have shown that tumor cells may be cultured from histologically normal brain at a distance greater than 4 cm from the gross tumor. Astrocytoma invasion is an active process that involves interactions with the host extracellular matrix (ECM), proteolytic modification of the ECM, and migration of the tumor cells into the modified matrix. 3 Members of the metalloproteinase, serine proteinase, and cysteine proteinase superfamilies have been linked to glioma invasion. 4 The cysteine proteinase cathepsin B (CatB) is expressed in gliomas in vitro 5 and immunohistochemical studies have demonstrated its presence in astrocytomas and glioblastomas in contrast to its absence from astrocytes in normal brain. 6,7 The expression and activity of CatB is higher in anaplastic astrocytomas and glioblastomas compared with low-grade tumors and normal brain 8 and high levels of CatB are positively correlated with poor survival. 9 Human glioblastoma cell lines also exhibit higher levels of CatB expression than lower grade astrocytomas 10 and the functional relevance of the enzyme is confirmed by a marked reduction in in vitro invasiveness of a glioblastoma cell line transfected with antisense CatB cDNA. 11 There is evide...

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Role for Cathepsin F in Invariant Chain Processing and Major Histocompatibility Complex Class II Peptide Loading by Macrophages

Cited by 220 publications

References 41 publications

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Asparagine Endopeptidase Is Not Essential for Class II MHC Antigen Presentation but Is Required for Processing of Cathepsin L in Mice

The Clinical Significance of Cathepsin S Expression in Human Astrocytomas

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