Functional Analysis of Cathepsin B-like Cysteine Proteases fromLeishmania donovani Complex

Somanna, Ashwini; Mundodi, Vasanthakrishna; Gedamu, Lashitew

doi:10.1074/jbc.m203034200

Cited by 98 publications

(52 citation statements)

References 38 publications

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“…Another cytokine, transforming growth factor beta (TGF-β), also has suppressive functions, and active VL is associated with increased plasma and mRNA levels of this cytokine [140]. The parasite-derived factor cathepsin-B, present in L. donovani , can activate TGF-β, which then has the potential to negatively impact on macrophage activity by lowering nitric oxide (NO) production [141], [142]. A better understanding of the precise mechanisms of TGF-β and IL-10 induction and activity during VL is required.…”

Section: Methodsmentioning

confidence: 99%

Immune Regulation during Chronic Visceral Leishmaniasis

et al. 2014

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Visceral leishmaniasis is a chronic parasitic disease associated with severe immune dysfunction. Treatment options are limited to relatively toxic drugs, and there is no vaccine for humans available. Hence, there is an urgent need to better understand immune responses following infection with Leishmania species by studying animal models of disease and clinical samples from patients. Here, we review recent discoveries in these areas and highlight shortcomings in our knowledge that need to be addressed if better treatment options are to be developed and effective vaccines designed.

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Section: Methodsmentioning

confidence: 99%

Immune Regulation during Chronic Visceral Leishmaniasis

et al. 2014

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“…Although we have proposed a role for cysteine protease Cat S in angiogenesis and presumably in tumor growth, we have had no direct in vivo evidence for or any mechanistic explanation of Cat S involvement. Several in vitro experiments demonstrated cysteine protease activities in the generation of anti-angiogenic endostatin (32,33), conversion of pro-angiogenic factor TGF-␤ (51,52), and activation of tumor invasionassociated urokinase-type plasminogen activator (53). It remains uncertain whether these in vitro activities of cysteine proteases have any pathophysiologic relevance in vivo.…”

Section: Discussionmentioning

confidence: 99%

Cathepsin S Controls Angiogenesis and Tumor Growth via Matrix-derived Angiogenic Factors

Wang

Sun

Kitamoto

et al. 2006

Journal of Biological Chemistry

247

196

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The cysteine protease cathepsin S is highly expressed in malignant tissues. By using a mouse model of multistage murine pancreatic islet cell carcinogenesis in which cysteine cathepsin activity has been functionally implicated, we demonstrated that selective cathepsin S deficiency impaired angiogenesis and tumor cell proliferation, thereby impairing angiogenic islet formation and the growth of solid tumors, whereas the absence of its endogenous inhibitor cystatin C resulted in opposite phenotypes. Although mitogenic vascular endothelial growth factor, transforming growth factor-␤1, and the anti-angiogenic endostatin levels in either serum or carcinoma tissue extracts did not change in cathepsin S-or cystatin C-null mice, tumor tissue basic fibroblast growth factor and serum type 1 insulin growth factor levels were higher in cystatin C-null mice, and serum type 1 insulin growth factor levels were also increased in cathepsin S-null mice. Furthermore, cathepsin S affected the production of type IV collagen-derived anti-angiogenic peptides and the generation of bioactive pro-angiogenic ␥2 fragments from laminin-5, revealing a functional role for cathepsin S in angiogenesis and neoplastic progression.Angiogenesis, the development of the microvasculature, is an essential process occurring under many pathological and physiological circumstances and depends on tightly controlled interactions between cells and extracellular matrix (ECM) 2 mediated by integral membrane proteins. These include integrins, which provide a link between ECM and the cytoskeleton, and extracellular proteases and their inhibitors, which mediate focal degradation of ECM components (1, 2), generate cell growth factors (3), and produce angiogenic regulatory factors (4).Lysosomal cysteine protease cathepsins have been shown to be highly expressed in human and murine tumors (5), where angiogenesis plays essential roles. Interruption of their expression either by antisense RNA (6) or RNA interference (7, 8) reduced tumor cell invasion, angiogenesis, and tumor growth. A recent study also demonstrated that inhibition of the activities of cysteine proteases with a broad inhibitor reduced angiogenesis and growth of pancreatic ␤-cell islet carcinoma in mice with an SV40 T antigen (Tag) transgene driven by the rat insulin II promoter (RIP1-Tag2) (9). Administration of JPM-ethyl ester (10), which affects all activities of cysteinyl cathepsins, significantly diminished the angiogenic switch, tumor burden, and tumor cell proliferation (11). However, many important questions are still unanswered; for example, which cathepsin(s) is the most important and by what mechanisms do these cysteinyl cathepsins affect tumor progression? Earlier studies suggested the importance of cathepsin (Cat) B in tumor angiogenesis and growth (6 -8). However, additional studies also demonstrated constitutive expression of Cat B in several cell types or tissues (12, 13). Therefore, cathepsins other than Cat B may also be involved in angiogenesis, tumor growth, cell proliferation, and...

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“…Previous studies examining the expression of cathepsin-B and L-like cysteine proteases in related kinetoplastids showed that the mRNA for the cathepsin L-like protease in Leishmania species was up-regulated in the intracellular amastigote stage, but the mRNA for the cathepsin B-like cysteine protease was equivalently expressed in the promastigote and amastigote stages (33)(34)(35). In T. cruzi, the mRNAs for cathepsin L and cathepsin B-like proteases are both up-regulated in the bloodstream trypomastigote stage (36,37).…”

Section: Tbcatb But Not Rhodesain Is Required For Degradation Ofmentioning

confidence: 99%

A Cathepsin B-like Protease Is Required for Host Protein Degradation in Trypanosoma brucei

Mackey

O'Brien

Greenbaum

et al. 2004

Journal of Biological Chemistry

119

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Identification and analysis of Clan CA (papain) cysteine proteases in primitive protozoa and metazoa have suggested that this enzyme family is more diverse and biologically important than originally thought. The protozoan parasite Trypanosoma brucei is the etiological agent of African sleeping sickness. The cysteine protease activity of this organism is a validated drug target as first recognized by the killing of the parasite with the diazomethane inhibitor Z-Phe-Ala-CHN 2 (where Z is benzyloxycarbonyl). Whereas the presumed target of this inhibitor was rhodesain (also brucipain, trypanopain), the major cathepsin L-like cysteine protease of T. brucei, genomic analysis has now identified tbcatB, a cathepsin B-like cysteine protease as a possible inhibitor target. The mRNA of tbcatB is more abundantly expressed in the bloodstream versus the procyclic form of the parasite. Induction of RNA interference against rhodesain did not result in an abnormal phenotype in cultured T. brucei. However, induction of RNA interference against tbcatB led to enlargement of the endosome, accumulation of fluorescein isothiocyanate-transferrin, defective cytokinesis after completion of mitosis, and ultimately the death of cultured parasites. Therefore, tbcatB, but not rhodesain, is essential for T. brucei survival in culture and is the most likely target of the diazomethane protease inhibitor Z-Phe-Ala-CHN 2 in T. brucei.

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Functional Analysis of Cathepsin B-like Cysteine Proteases fromLeishmania donovani Complex

Cited by 98 publications

References 38 publications

Immune Regulation during Chronic Visceral Leishmaniasis

Immune Regulation during Chronic Visceral Leishmaniasis

Cathepsin S Controls Angiogenesis and Tumor Growth via Matrix-derived Angiogenic Factors

A Cathepsin B-like Protease Is Required for Host Protein Degradation in Trypanosoma brucei

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