Cysteine peptidases as virulence factors of Leishmania

Mottram, Jeremy C.; Coombs, Graham H.; Alexander, James

doi:10.1016/j.mib.2004.06.010

Cited by 220 publications

(203 citation statements)

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“…Proteolytic enzymes or proteinases play an essential role in the parasite's survival. These molecules have been identified as promising targets for the development of a rational antileishmanial chemotherapy (Coombs et al 2001;Klemba and Goldberg 2002;Mottram et al 2004;McKerrow et al 2008;McLuskey et al 2010). It is within this context that we reported the presence of aspartyl proteinase activity in promastigotes of Leishmania mexicana and Leishmania infantum (Valdivieso et al 2007(Valdivieso et al , 2010, which is sensitive to diazoacetyl-DL-norleucin methyl ester (DAN) and the specific HIV aspartyl proteinase inhibitors, Ac-Leu-Val-Phenylalaninal, Nelfinavir (NFV), and Saquinavir (Valdivieso et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Ddi1-like protein from Leishmania major is an active aspartyl proteinase

Perteguer

Gómez‐Puertas

Cañavate

et al. 2013

Cell Stress and Chaperones

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Eukaryotic cells respond to DNA damage by activating damage checkpoint pathways, which arrest cell cycle progression and induce gene expression. We isolated a full-length cDNA encoding a 49-kDa protein from Leishmania major, which exhibited significant deduced amino acid sequence homology with the annotated Leishmania sp. DNA damage-inducible (Ddi1-like) protein, as well as with the Ddi1 protein from Saccharomyces cerevisiae. In contrast to the previously described Ddi1 protein, the protein from L. major displays three domains: (1) an NH2-terminal ubiquitin like; (2) a COOH terminal ubiquitinassociated; (3) a retroviral aspartyl proteinase, containing the typical D[S/T]G signature. The function of the L. major Ddi1-like recombinant protein was investigated after expression in baculovirus/insect cells and biochemical analysis, revealing preferential substrate selectivity for aspartyl proteinase A 2 family substrates, with optimal activity in acidic conditions. The proteolytic activity was inhibited by aspartyl proteinase inhibitors. Molecular modeling of the retroviral domain of the Ddi1-like Leishmania protein revealed a dimer structure that contained a double AspSer-Gly-Ala amino acid sequence motif, in an almost identical geometry to the exhibited by the homologous retroviral aspartyl protease domain of yeast Ddi1 protein. Our results indicate that the isolated Ddi1-like protein is a functional aspartyl proteinase in L. major, opening possibility to be considered as a potential target for novel antiparasitic drugs.

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Section: Introductionmentioning

confidence: 99%

Ddi1-like protein from Leishmania major is an active aspartyl proteinase

Perteguer

Gómez‐Puertas

Cañavate

et al. 2013

Cell Stress and Chaperones

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“…Whereas the catalytic dyad CH is sufficient for clan CD; however, other cysteine peptidases possess an additional highly conserved amino acid that is involved in the catalytic mechanism. For instance, either an asparagine or aspartic acid residue is present in clan CA, serving to orientate the active site histidine [57].…”

Section: Cysteine Peptidase Familiesmentioning

confidence: 99%

“…Thus, they have attracted considerable inter-est as targets for the design of new chemotherapeutic agents and vaccines [57]. Leishmania spp.…”

Section: Cysteine Peptidasesmentioning

confidence: 99%

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Biological Roles of Peptidases in Trypanosomatids~!2009-11-26~!2010-02-15~!2010-03-18~!

Vermelho

Branquinha²,

d’Avila-Levy³

et al. 2010

TOPARAJ

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Abstract:In this review, we report the recent developments in the characterization of peptidases and their possible biological functions in the Trypanosomatidae family. The focus will be on peptidases from Trypanosoma cruzi, Leishmania spp., African trypanosomes and plant and insect trypanosomatids. There are numerous events in parasite development where the involvement of peptidases has been established, and they will be approached in the present review. Also in this review we will discuss the central roles have been proposed for peptidases in diverse processes such as virulence, host cell interaction and invasion, catabolism of host proteins, differentiation, cell cycle progression and both stimulation and evasion of host immune responses.

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“…Cysteine proteases (CPs) are expressed by and important for the growth and differentiation of multiple Leishmania spp. (20). Of the three classes of CPs (CP-A, -B, and -C), CP-B is the most well studied in Leishmania mexicana and is crucial for the intracellular growth of amastigotes; released CP-B may be important for the cleavage of host proteins within phagolysosomes (2, 9, 29).…”

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confidence: 99%

Fibronectin Binding and Proteolytic Degradation byLeishmaniaand Effects on Macrophage Activation

et al. 2008

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Infection by vector-borne protozoa of the genus Leishmania occurs by the deposition of parasites within the skin of the mammalian host, where they eventually bind to and are phagocytized by M s. Our previous work supported the idea that parasites can interact with extracellular matrix and basement membrane proteins, such as fibronectin (FN), within the skin, leading to enhanced invasion. In this report, we extend these findings and show that both promastigotes and amastigotes of Leishmania species can bind directly to soluble FN and laminin (LM) and that promastigotes express a distinct surface protein of ϳ60 kDa that binds both FN and LM. Promastigotes of multiple Leishmania species can rapidly degrade FN by using surface-localized and secreted metalloprotease (leishmanolysin). FN degradation at the surfaces of amastigotes is leishmanolysin dependent, whereas both secreted leishmanolysin and cysteine protease B contribute to extracellular FN degradation. Leishmania-degraded FN decreased the production of reactive oxygen intermediates by parasiteinfected macrophages and affected the accumulation of intracellular parasites. These findings show that both parasite stages of Leishmania species bind to and proteolytically degrade FN at the parasite surface and distantly through secreted proteases and that degraded forms of FN can influence the activation state of parasite-infected macrophages.Leishmania species are vector-borne pathogenic protozoa which cause considerable worldwide morbidity and mortality. Infection is initiated by the deposition of infective flagellated promastigotes within the skin of the mammalian host during the feeding of infected sand flies. Within host macrophages (M s), parasites differentiate into and replicate as intracellular, aflagellate amastigotes, eventually escaping extracellularly, where they are phagocytized by uninfected M s (7). Reactiveoxygen intermediates (ROI) and reactive-nitrogen intermediates are important for intraphagolysosomal parasite killing at early and late phases of infection, respectively (21).The cell surface metalloproteases (also known as leishmanolysin, gp63, and msp) of Leishmania spp. are broad-spectrum, zinc-dependent proteases that aid parasite evasion of innate host immune factors, such as complement, and act as adhesins of host M s (5, 6, 16). Leishmanolysin also protects amastigotes from nonoxidative degradation within M s (8, 16). Cysteine proteases (CPs) are expressed by and important for the growth and differentiation of multiple Leishmania spp. (20). Of the three classes of CPs (CP-A, -B, and -C), CP-B is the most well studied in Leishmania mexicana and is crucial for the intracellular growth of amastigotes; released CP-B may be important for the cleavage of host proteins within phagolysosomes (2, 9, 29).We have previously shown that the migration of Leishmania spp. through the extracellular matrix (ECM) in vitro is due to the leishmanolysin-mediated proteolysis of fibronectin (FN) and collagen type IV (18). FN is a large, multifunctional protein, ...

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Cysteine peptidases as virulence factors of Leishmania

Cited by 220 publications

References 50 publications

Ddi1-like protein from Leishmania major is an active aspartyl proteinase

Ddi1-like protein from Leishmania major is an active aspartyl proteinase

Biological Roles of Peptidases in Trypanosomatids~!2009-11-26~!2010-02-15~!2010-03-18~!

Fibronectin Binding and Proteolytic Degradation byLeishmaniaand Effects on Macrophage Activation

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