In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 18, No. 2 ( 2022-2-1), p. e1010293-
Abstract:
Many biosynthetic pathways produce pyrophosphate (PPi) as a by-product, which is cytotoxic if accumulated at high levels. Pyrophosphatases play pivotal roles in PPi detoxification by converting PPi to inorganic phosphate. A number of apicomplexan parasites, including Toxoplasma gondii and Cryptosporidium parvum , express a PPi-dependent phosphofructokinase (PPi-PFK) that consumes PPi to power the phosphorylation of fructose-6-phosphate. However, the physiological roles of PPi-PFKs in these organisms are not known. Here, we report that Toxoplasma expresses both ATP- and PPi-dependent phosphofructokinases in the cytoplasm. Nonetheless, only PPi-PFK was indispensable for parasite growth, whereas the deletion of ATP-PFK did not affect parasite proliferation or virulence. The conditional depletion of PPi-PFK completely arrested parasite growth, but it did not affect the ATP level and only modestly reduced the flux of central carbon metabolism. However, PPi-PFK depletion caused a significant increase in cellular PPi and decreased the rates of nascent protein synthesis. The expression of a cytosolic pyrophosphatase in the PPi-PFK depletion mutant reduced its PPi level and increased the protein synthesis rate, therefore partially rescuing its growth. These results suggest that PPi-PFK has a major role in maintaining pyrophosphate homeostasis in T . gondii . This role may allow PPi-PFK to fine-tune the balance of catabolism and anabolism and maximize the utilization efficiency for carbon nutrients derived from host cells, increasing the success of parasitism. Moreover, PPi-PFK is essential for parasite propagation and virulence in vivo but it is not present in human hosts, making it a potential drug target to combat toxoplasmosis.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1010293
DOI:
10.1371/journal.ppat.1010293.g001
DOI:
10.1371/journal.ppat.1010293.g002
DOI:
10.1371/journal.ppat.1010293.g003
DOI:
10.1371/journal.ppat.1010293.g004
DOI:
10.1371/journal.ppat.1010293.g005
DOI:
10.1371/journal.ppat.1010293.g006
DOI:
10.1371/journal.ppat.1010293.g007
DOI:
10.1371/journal.ppat.1010293.g008
DOI:
10.1371/journal.ppat.1010293.s001
DOI:
10.1371/journal.ppat.1010293.s002
DOI:
10.1371/journal.ppat.1010293.s003
DOI:
10.1371/journal.ppat.1010293.s004
DOI:
10.1371/journal.ppat.1010293.s005
DOI:
10.1371/journal.ppat.1010293.s006
DOI:
10.1371/journal.ppat.1010293.s007
DOI:
10.1371/journal.ppat.1010293.s008
DOI:
10.1371/journal.ppat.1010293.s009
DOI:
10.1371/journal.ppat.1010293.s010
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2205412-1