Plasmodium falciparum signal peptidase is regulated by phosphorylation and required for intra-erythrocytic growth

Tuteja, Renu; Pradhan, Arun; Sharma, Sarsij

doi:10.1016/j.molbiopara.2007.10.007

Cited by 24 publications

(17 citation statements)

References 51 publications

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“…The central players in this secretion system are a group of signal peptidases that are capable of cleaving signal sequences from the target proteins that can then be routed to their destinations. Five signal peptidases have been predicted and characterized, constituting the signal peptidase complex (SPC) in P. falciparum [3,106,107]. Three of these peptidases have association partners: PfSPC21 (MAL13P1.167) has 120 associations; the putative microsomal signal peptidase (PF14_0317) has five associations; and the putative SPC22 (PFI0215c) has five associations (Figure 6).…”

Section: Resultsmentioning

confidence: 99%

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Protease-associated cellular networks in malaria parasite Plasmodium falciparum

et al. 2011

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BackgroundMalaria continues to be one of the most severe global infectious diseases, responsible for 1-2 million deaths yearly. The rapid evolution and spread of drug resistance in parasites has led to an urgent need for the development of novel antimalarial targets. Proteases are a group of enzymes that play essential roles in parasite growth and invasion. The possibility of designing specific inhibitors for proteases makes them promising drug targets. Previously, combining a comparative genomics approach and a machine learning approach, we identified the complement of proteases (degradome) in the malaria parasite Plasmodium falciparum and its sibling species [1-3], providing a catalog of targets for functional characterization and rational inhibitor design. Network analysis represents another route to revealing the role of proteins in the biology of parasites and we use this approach here to expand our understanding of the systems involving the proteases of P. falciparum.ResultsWe investigated the roles of proteases in the parasite life cycle by constructing a network using protein-protein association data from the STRING database [4], and analyzing these data, in conjunction with the data from protein-protein interaction assays using the yeast 2-hybrid (Y2H) system [5], blood stage microarray experiments [6-8], proteomics [9-12], literature text mining, and sequence homology analysis. Seventy-seven (77) out of 124 predicted proteases were associated with at least one other protein, constituting 2,431 protein-protein interactions (PPIs). These proteases appear to play diverse roles in metabolism, cell cycle regulation, invasion and infection. Their degrees of connectivity (i.e., connections to other proteins), range from one to 143. The largest protease-associated sub-network is the ubiquitin-proteasome system which is crucial for protein recycling and stress response. Proteases are also implicated in heat shock response, signal peptide processing, cell cycle progression, transcriptional regulation, and signal transduction networks.ConclusionsOur network analysis of proteases from P. falciparum uses a so-called guilt-by-association approach to extract sets of proteins from the proteome that are candidates for further study. Novel protease targets and previously unrecognized members of the protease-associated sub-systems provide new insights into the mechanisms underlying parasitism, pathogenesis and virulence.

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Section: Resultsmentioning

confidence: 99%

“…We previously identified a single copy of calpain PfCalp (MAL13P1.310) in P. falciparum genome [3,106,107]. Calpain is crucial for signal transduction, cell cycle regulation, differentiation, development, and cell-cell communication from bacteria to humans.…”

Section: Resultsmentioning

confidence: 99%

Protease-associated cellular networks in malaria parasite Plasmodium falciparum

et al. 2011

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“…Signal peptidases are membrane-bound endopeptidases that have an important role in the transport and maturation of parasite proteins [57](55).…”

Section: Discussionmentioning

confidence: 99%

Signaling transcript profile of the asexual intraerythrocytic development cycle of Plasmodium falciparum induced by melatonin and cAMP

et al. 2016

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According to the World Health Organization (WHO), Plasmodium falciparum is the deadliest parasite among all species. This parasite possesses the ability to sense molecules, including melatonin (MEL) and cAMP, and modulate its cell cycle accordingly. MEL synchronizes the development of this malaria parasite by activating several cascades, including the generation of the second messenger cAMP. Therefore, we performed RNA sequencing (RNA-Seq) analysis in P. falciparum erythrocytic stages (ring, trophozoite and schizont) treated with MEL and cAMP. To investigate the expression profile of P. falciparum genes regulated by MEL and cAMP, we performed RNA-Seq analysis in three P. falciparum strains (control, 3D7; protein kinase 7 knockout, PfPK7-; and PfPK7 complement, PfPK7C). In the 3D7 strain, 38 genes were differentially expressed upon MEL treatment; however, none of the genes in the trophozoite (T) stage PfPK7- knockout parasites were differentially expressed upon MEL treatment for 5 hours compared to untreated controls, suggesting that PfPK7 may be involved in the signaling leading to differential gene expression. Moreover, we found that MEL modified the mRNA expression of genes encoding membrane proteins, zinc ion-binding proteins and nucleic acid-binding proteins, which might influence numerous functions in the parasite. The RNA-Seq data following treatment with cAMP show that this molecule modulates different genes throughout the intraerythrocytic cycle, namely, 75, 101 and 141 genes, respectively, in the ring (R), T and schizont (S) stages. Our results highlight P. falciparum's perception of the external milieu through the signaling molecules MEL and cAMP, which are able to drive to changes in gene expression in the parasite.

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“…The seventh protein, similar to signal peptidase complex subunit 2 (SPCS2), is a serine protease that cleaves signal peptides from translocated precursor proteins [58]. However, its role in cancer or other diseases remains to be uncovered.…”

Section: Numbermentioning

confidence: 99%