Lysosomal cysteine proteases regulate antigen presentation

Honey, Karen; Rudensky, Alexander Y.

doi:10.1038/nri1110

Cited by 395 publications

(317 citation statements)

References 111 publications

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“…[1][2][3]. Studies with broad spectrum cysteine protease inhibitors such as leupeptin suggested the involvement of both cysteine and noncysteine proteases (4 -6).…”

mentioning

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

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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“…[1][2][3]. Studies with broad spectrum cysteine protease inhibitors such as leupeptin suggested the involvement of both cysteine and noncysteine proteases (4 -6).…”

mentioning

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

104

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“…Cathepsin L is a lysosomal protease that plays an important role in the intracellular protein degradation, activation of enzyme precursors, and tumor invasion (8,9). Normally located in lysosomes of mammalian cells, it can be secreted from the cell under certain conditions.…”

mentioning

confidence: 99%

Podocyte Migration during Nephrotic Syndrome Requires a Coordinated Interplay between Cathepsin L and α3 Integrin

Reiser¹,

Oh²,

Shirato³

et al. 2004

Journal of Biological Chemistry

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163

135

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Podocyte foot process effacement and disruption of the slit diaphragm are typically associated with glomerular proteinuria and can be induced in rats by the injection of puromycin aminonucleoside. Here, we show that the induction of puromycin aminonucleoside nephrosis involves podocyte migration conducted by a coordinated interplay between the cysteine protease cathepsin L and ␣ 3 integrin. Puromycin aminonucleoside treatment up-regulates cathepsin L expression in podocytes in vivo as well as expression and enzymatic activity of cathepsin L in podocytes in vitro. Isolated podocytes from mice lacking cathepsin L are protected from cell puromycin aminonucleoside-induced cell detachment. The functional significance of cathepsin L expression was underscored by the observation that puromycin aminonucleoside-induced cell migration was slowed down in cathepsin L-deficient podocytes and by the preservation of cell-cell contacts and expression of vital slit diaphragm protein CD2AP. Cathepsin L expression and activity were induced in podocytes lacking ␣ 3 integrin. Similarly, acute functional inhibition of ␣ 3 integrin in wild type podocytes with a blocking antibody increased the expression of cathepsin L activity. Downregulation of ␣ 3 integrin protected against puromycin aminonucleoside-induced podocyte detachment. In summary, these data establish that podocyte foot process effacement is a migratory event involving a novel interplay between cathepsin L and ␣ 3 integrin.Glomerular podocytes serve as a final barrier to urinary protein loss by the formation and maintenance of podocyte foot processes and the interposed slit diaphragm (SD) 1 All forms of nephrotic syndrome are characterized by podocyte foot process (FP) effacement and/or molecular reorganization of the slit diaphragm (1). FP effacement requires a precise interplay of multiple cellular functions including structural alterations of the cytoskeleton, movement of FP over the basement membrane, and reconstruction of the slit diaphragm (1). The discovery of several novel podocyte proteins and their mutation analysis including nephrin (2), CD2AP (3), ␣-actinin-4 (4), podocin (5), neph1 (6), and FAT (7) have shed light on the pathogenesis of FP effacement and proteinuria and emphasized the critical role of podocyte FP and the SD in maintaining the function of the glomerular filtration barrier.

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“…To test whether NucNeoR presentation is mediated by a similar pathway, the NeoR and NucNeoR transfectants were incubated for 20 h with 3-MA, a specific inhibitor of autophagosome formation [10], or leupeptin and chloroquine to inhibit lysosomal degradation [13]. After incubation, the inhibitors were removed by repeated washing to preclude interference with T cell functions; the cells were immediately fixed with paraformaldehyde and subsequently probed with the NeoR-specific T cells.…”

Section: Efficient Presentation Of Nuclear Neor On Mhc Class IImentioning

confidence: 99%

Endogenous presentation of a nuclear antigen on MHC class II by autophagy in the absence of CRM1‐mediated nuclear export

Riedel

Nimmerjahn²,

Burdach

et al. 2008

Eur J Immunol

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Accumulating evidence suggests that intracellular antigens are endogenously presented on MHC class II, but it is still unknown whether antigens within different subcellular compartments are presented with similar efficiency, and via the same or different pathways. We have previously shown that endogenous MHC class II presentation of the cytosolic bacterial antigen neomycin phosphotransferase II (NeoR) is mediated by autophagy. Here, we addressed whether secluding NeoR from this cytoplasmic pathway by directing the protein into the cell nucleus (NucNeoR) would affect antigen presentation. Unexpectedly, NucNeoR was presented at least as efficiently as the cytosolic version of the antigen. Furthermore, presentation of NucNeoR was also dependent on autophagocytosis and lysosomal processing, indicating that both antigens were presented via the same pathway. Inhibition of CRM1-mediated nuclear export did not impede antigen presentation, indicating that NucNeoR gained access to this autophagy-dependent MHC class II presentation pathway by a CRM1-independent route. Thus, this endogenous presentation pathway broadens the spectrum of intracellular antigens surveyed by CD4 + T cells by efficiently sampling cytoplasmic as well as nuclear antigens.

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Lysosomal cysteine proteases regulate antigen presentation

Cited by 395 publications

References 111 publications

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

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

Podocyte Migration during Nephrotic Syndrome Requires a Coordinated Interplay between Cathepsin L and α3 Integrin

Endogenous presentation of a nuclear antigen on MHC class II by autophagy in the absence of CRM1‐mediated nuclear export

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