Non-canonical Maturation of Two Papain-family Proteases in Toxoplasma gondii

Dou, Zhicheng; Coppens, Isabelle; Carruthers, Vern B.

doi:10.1074/jbc.m112.443697

Cited by 35 publications

(76 citation statements)

References 44 publications

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“…The VAC is a proteolytic compartment that houses cathepsin-like cysteine proteases, such as TgCPL and TgCPB (11,39). Using a live-cell-imaging approach, we demonstrated that the VAC is a highly dynamic compartment.…”

Section: Discussionmentioning

confidence: 99%

“…The function of proteases, such as TgCPL and TgCPB, and the functions of the VAC more generally remain poorly defined. Knockout of TgCPL partially impairs the proteolytic maturation of TgCPB and certain microneme proteins, suggesting a role in protein activation (11,39). While falcipains are maturases for plasmepsin aspartyl proteases in the DV (43), they have not been linked to the maturation of microneme proteins.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of the Chloroquine Resistance Transporter Homologue in Toxoplasma gondii

et al. 2014

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Characterization of the Chloroquine Resistance Transporter Homologue in Toxoplasma gondii

et al. 2014

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“…Additionally, G. duodenalis cathepsin cysteine proteases may require activation via separate proteases. For example, Toxoplasma gondii catB proteases require proteolytic activation by the parasite's catL cysteine proteases (96). Additional research is required to examine the structure and substrate specificities of G. duodenalis catB proteases to determine whether these factors exhibit unique substrate specificities and, furthermore, if other proteases participate in the degradation of CXCL8.…”

Section: Discussionmentioning

confidence: 99%

Giardia duodenalis Cathepsin B Proteases Degrade Intestinal Epithelial Interleukin-8 and Attenuate Interleukin-8-Induced Neutrophil Chemotaxis

et al. 2014

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“…In particular, the aminopeptidase activity can activate serine proteases by removing inhibitory short amino-terminal peptides (61). Proteolytic activation by cysteine proteases also occurs in T. gondii (58). Thus, the defects in ⌬cth4 cells may reflect the failure to activate additional enzymes, rather than the direct action of Cth4p on Grl proproteins.…”

Section: Fig 11mentioning

confidence: 99%

“…In addition, the current data do not distinguish between Cth4p acting directly upon proGrl substrates or being indirectly responsible for processing, e.g., by activating another enzyme which directly acts upon proGrls. In T. gondii, a cathepsin L enzyme, TgCPL, processes dissimilar substrates that are moreover targeted to two different compartments: secretory organelles (micronemes) and an acidic compartment termed the plant-like vacuole (PLV) (57,58).…”

Section: Fig 11mentioning

confidence: 99%

Secretion of Polypeptide Crystals from Tetrahymena thermophila Secretory Organelles (Mucocysts) Depends on Processing by a Cysteine Cathepsin, Cth4p

2015

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In many organisms, sophisticated mechanisms facilitate release of peptides in response to extracellular stimuli. In the ciliate Tetrahymena thermophila, efficient peptide secretion depends on specialized vesicles called mucocysts that contain dense crystalline cores that expand rapidly during exocytosis. Core assembly depends of endoproteolytic cleavage of mucocyst proproteins by an aspartyl protease, cathepsin 3 (CTH3). Here, we show that a second enzyme identified by expression profiling, Cth4p, is also required for processing of proGrl proteins and for assembly of functional mucocysts. Cth4p is a cysteine cathepsin that localizes partially to endolysosomal structures and appears to act downstream of, and may be activated by, Cth3p. Disruption of CTH4 results in cells (⌬cth4) that show aberrant trimming of Grl proproteins, as well as grossly aberrant mucocyst exocytosis. Surprisingly, ⌬cth4 cells succeed in assembling crystalline mucocyst cores. However, those cores do not undergo normal directional expansion during exocytosis, and they thus fail to efficiently extrude from the cells. We could phenocopy the ⌬cth4 defects by mutating conserved catalytic residues, indicating that the in vivo function of Cth4p is enzymatic. Our results indicate that as for canonical proteins packaged in animal secretory granules, the maturation of mucocyst proproteins involves sequential processing steps. The ⌬cth4 defects uncouple, in an unanticipated way, the assembly of mucocyst cores and their subsequent expansion and thereby reveal a previously unsuspected aspect of polypeptide secretion in ciliates. R egulated secretion of peptides from intracellular stores plays many key roles in intercellular communication and tissue coordination in animals (1). A highly specialized organelle in neuroendocrine cells, the secretory granule, is required for peptide generation, storage, and release (2). The bioactive peptides are generated during secretory granule formation by the action of proteolytic enzymes on polypeptide precursors (3). Proteolytic processing occurs in a post-trans-Golgi network (TGN) compartment, the immature granule, to which propeptides are sorted away from bulk protein traffic, and is a multistep process involving several classes of enzymes (4-6). The best studied among these are a family of serine proteases called prohormone convertases (7). Related to bacterial subtilisins, prohormone convertases (PCs) catalyze endoproteolytic cleavage at defined motifs in their substrates. The products of that cleavage can then undergo trimming, for which one important factor is carboxypeptidase E (CPE) (8). Defects in both PCs and CPE are linked with disease (9, 10).Signaling via peptide secretion appears to be widespread in eukaryotes and has also been well documented for fungi, amoebozoa, and plants(11-13). In the oligohymenophorean ciliates Tetrahymena thermophila and Paramecium tetraurelia, regulated peptide secretion occurs from organelles that share striking similarities with secretory granules in animals (14, 15), although...

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Non-canonical Maturation of Two Papain-family Proteases in Toxoplasma gondii

Cited by 35 publications

References 44 publications

Characterization of the Chloroquine Resistance Transporter Homologue in Toxoplasma gondii

Characterization of the Chloroquine Resistance Transporter Homologue in Toxoplasma gondii

Giardia duodenalis Cathepsin B Proteases Degrade Intestinal Epithelial Interleukin-8 and Attenuate Interleukin-8-Induced Neutrophil Chemotaxis

Secretion of Polypeptide Crystals from Tetrahymena thermophila Secretory Organelles (Mucocysts) Depends on Processing by a Cysteine Cathepsin, Cth4p

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