A novel cell penetrating aspartic protease inhibitor blocks processing and presentation of tetanus toxoid more efficiently than pepstatin A

Zaidi, Nousheen; Burster, Timo; Sommandas, Vinod; Herrmann, Timo; Boehm, Bernhard O.; Driessen, Christoph; Voelter, Wolfgang; Kalbacher, Hubert

doi:10.1016/j.bbrc.2007.09.114

Cited by 32 publications

(28 citation statements)

References 23 publications

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“…One of the major problems in using pepstatin is its poor solubility and inefficient membrane penetration. To overcome these problems, various analogs were synthesized to improve its bioavailability and selectivity but thus far these analogs have not seen common use in biological research [131,132]. In addition to its role in inhibiting protease activities, other nonspecific effects of pepstatin A could not be ruled out.…”

Section: Apoptosismentioning

confidence: 99%

Cathepsin D—Many functions of one aspartic protease

Beneš

Větvička

Fusek

2008

Critical Reviews in Oncology/Hematology

541

474

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For years, it has been held that cathepsin D (CD) is involved in rather nonspecific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans.In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling.Moreover, procathepsin D, secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy.Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell -pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above mentioned processes.In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.

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Section: Apoptosismentioning

confidence: 99%

Cathepsin D—Many functions of one aspartic protease

Beneš

Větvička

Fusek

2008

Critical Reviews in Oncology/Hematology

541

474

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“…CatD is expressed in all cells (except erythrocytes), whereas CatE expression is restricted to APC (Bennett et al, 1992; Burster et al, 2008; Chain et al, 2005; Hewitt et al, 1997; Moss et al, 2005; Zaidi et al, 2007). In APC, CatE is localized to endosomes, while CatD is primarily located in lysosomes (for review see (Zaidi and Kalbacher, 2008)).…”

Section: Cathepsins Of the Cysteine And Aspartyl Protease Classesmentioning

confidence: 99%

Cathepsin G: Roles in antigen presentation and beyond

Burster¹,

Macmillan²,

Hou³

et al. 2010

Molecular Immunology

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Summary Contributions from multiple cathepsins within endosomal antigen processing compartments are necessary to process antigenic proteins into antigenic peptides. Cysteine and aspartyl cathepsins have been known to digest antigenic proteins. A role for the serine protease, Cathepsin G (CatG), in this process has been described only recently, although CatG has long been known to be a granule-associated proteolytic enzyme of neutrophils. In line with a role for this enzyme in antigen presentation, CatG is found in endocytic compartments of a variety of antigen presenting cells. CatG is found in primary human monocytes, B cells, myeloid dendritic cells 1 (mDC1), mDC2, plasmacytoid DC (pDC), and murine microglia, but is not expressed in B cell lines or monocyte-derived DC. Purified CatG can be internalized into endocytic compartments in CatG non-expressing cells, widening the range of cells where this enzyme may play a role in antigen processing. Functional assays have implicated CatG as a critical enzyme in processing of several antigens and autoantigens. In this review, historical and recent data on CatG expression, distribution, function and involvement in disease will be summarized and discussed, with a focus on its role in antigen presentation and immune-related events.

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“…The pepstatin-A-penetratin (PepA-P) conjugate is a highly efficient cell-permeable aspartyl protease inhibitor which inhibits tetanus toxoid C-fragment (TTC) processing in primary human myeloid dendritic cells (mDC1) and B cells, indicating that CatD or CatE participates in processing of TTC in mDC and B cells [10]. These findings were differentiated by using phorbol 12-myristate 13-acetate (PMA), suggesting that CatE participates in antigen processing in primary B cells [11].…”

Section: Introductionmentioning

confidence: 99%