Cathepsin Proteases in Toxoplasma gondii

Abstract

Cysteine proteases are important for the growth and survival of apicomplexan parasites that infect humans. The apicomplexan Toxoplasma gondii expresses five members of the C1 family of cysteine proteases, including one cathepsin L-like (TgCPL), one cathepsin B-like (TgCPB), and three cathepsin C-like (TgCPC1, 2 and 3) proteases. Recent genetic, biochemical and structural studies reveal that cathepsins function in microneme and rhoptry protein maturation, host cell invasion, replication, and nutrient acquisition.. Here, we review the key features and roles of T. gondii cathepsins and discuss the therapeutic potential for specific inhibitor development.

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“…It is classified into seven categories based on the key catalase residues in an active location: Aspartic, cysteine, glutamic, serine, threonine, metallic, and chromium, which can be divided into more families [16]. This enzyme is important for the growth and survival of parasites in humans [17]. Lagal et al reported that host cell invasion by T. gondii is critically dependent on adhesive proteins secreted from the micronemes.…”

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“…Cathepsin proteases act clasically as lysosomal hydrolases that digest endogenous and exogenous endocytosed polypeptides [706] . They function in microneme and rhoptry protein maturation, host cell invasion, replication, and nutrient acquisition [707,708] . Que et al [705] showed that the TgCatB, toxopain-1, was localized to rhoptries (secretory organelles required for parasite invasion into cells), and was critical for parasite invasion and rhoptry protein processing.…”

“…It was demonstrated that T. gondii tachyzoites ingested host cytosolic proteins and digested them using CatL and other proteases within its endolysosomal system [708] . Both virulent type I and avirulent type II strain parasites ingested and digested hostderived proteins, indicating that the pathway is not restricted only to highly virulent strains.…”

“…T. gondii cathepsins were required for peptide degradation in the parasitophorous vacuole (PV), as the degradation of the marker protein, E. coli β-lactamase, secreted into the PV of transgenic tachyzoites was completely inhibited by the CatC inhibitor [707] . Tables 26 and 27 summarized classes and specific cathepsin-like proteases of T. gondii proteases, their function and localization, and the parasite stage expressions [708,712] . TgCPC1 was found to be the most highly expressed cathepsin mRNA in tachyzoites, and three cathepsins, TgCPB, TgCPC1 and TgCPC2, were undetectable in in vivo bradyzoites [708] .…”

“…Tables 26 and 27 summarized classes and specific cathepsin-like proteases of T. gondii proteases, their function and localization, and the parasite stage expressions [708,712] . TgCPC1 was found to be the most highly expressed cathepsin mRNA in tachyzoites, and three cathepsins, TgCPB, TgCPC1 and TgCPC2, were undetectable in in vivo bradyzoites [708] . Infection of the host vascular endothelial cells by T. gondii tachyzoites may be an important source of additional cathepsins activity, which will be superimposing on the host cell normal/ pathologic cathepsin activities.…”