An FtsH Protease Is Recruited to the Mitochondrion of Plasmodium falciparum

Abstract

The two organelles, apicoplast and mitochondrion, of the malaria parasite Plasmodium falciparum have unique morphology in liver and blood stages; they undergo complex branching and looping prior to division and segregation into daughter merozoites. Little is known about the molecular processes and proteins involved in organelle biogenesis in the parasite. We report the identification of an AAA+/FtsH protease homolog (PfFtsH1) that exhibits ATP- and Zn2+-dependent protease activity. PfFtsH1 undergoes processing, forms oligomeric assemblies, and is associated with the membrane fraction of the parasite cell. Generation of a transfectant parasite line with hemagglutinin-tagged PfFtsH1, and immunofluorescence assay with anti-PfFtsH1 Ab demonstrated that the protein localises to P. falciparum mitochondria. Phylogenetic analysis and the single transmembrane region identifiable in PfFtsH1 suggest that it is an i-AAA like inner mitochondrial membrane protein. Expression of PfFtsH1 in Escherichia coli converted a fraction of bacterial cells into division-defective filamentous forms implying a sequestering effect of the Plasmodium factor on the bacterial homolog, indicative of functional conservation with EcFtsH. These results identify a membrane-associated mitochondrial AAA+/FtsH protease as a candidate regulatory protein for organelle biogenesis in P. falciparum.

Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens

“… ( A ) Western blot of Pf FtsH-FLAG levels in parasites with and without an apicoplast and with and without aTC induction. Consistent with the previous report of Pf FtsH1 C -terminal processing, we were unable to detect full-length Pf FtsH1-FLAG using anti-FLAG in parasites with intact apicoplasts (lane 1) ( Tanveer et al, 2013 ; Karnataki et al, 2009 ). However, in parasites missing apicoplasts, full-length Pf FtsH1-FLAG was detectable, suggesting that Pf FtsH1 processing requires the apicoplast (lanes 2).…”

“…One of these, Pf FtsH1 (Pf3D7_1239700) is most closely related to Tg FtsH1 by phylogenetic analysis ( Tanveer et al, 2013 ). Unlike Tg FtsH1, Pf FtsH1 was previously reported to localize to the mitochondrion, not the apicoplast ( Tanveer et al, 2013 ). However the same study reported that, like Tg FtsH1, Pf FtsH1 undergoes processing.…”

Plasmodium falciparum OTU-like cysteine protease (PfOTU) is essential for apicoplast homeostasis and associates with noncanonical role of Atg8

“…In the present study, we have identified functional role of a novel ovarian tumour unit (OTU) domain-containing cysteine protease of Plasmodium falciparum (PfOTU). Organelle proteases have been shown to play essential roles in growth and segregation of parasite organelles, and these are suggested to be potential drug targets (Jain et al, 2013;Rathore et al, 2010;Tanveer et al, 2013). Detailed studies showed vesicular localization of PfOTU and its association with the apicoplast.…”

“…Understanding of unique metabolic pathways, which are functionally important for maintenance and homeostasis of these organelles, may help us to identify novel drug targets. Organelle proteases have been shown to play essential roles in growth and segregation of parasite organelles, and these are suggested to be potential drug targets (Jain et al, 2013;Rathore et al, 2010;Tanveer et al, 2013). The apicoplast, relict plastid in the parasite, was acquired through secondary endosymbiosis during parasite evolution.…”

A single point mutation in the Plasmodium falciparum ftsh1 metalloprotease confers actinonin resistance

“…This might mean that actinonin kills malaria parasites through a mechanism not involving PfFtsH1, perhaps even inhibition of PfPDF. Compounding this uncertainty is a report that PfFtsH1 is localized in the mitochondrion 8 , which would not be consistent with the demonstrated impact of actinonin on the malaria parasite apicoplast 4 7 .…”