Toxoplasma gondii is an important opportunistic pathogen, affecting up to one-third of untreated AIDS patients worldwide. The parasite possesses a unique and essential organelle called the apicoplast, which is genetically and functionally related to chloroplasts. Because the human host lacks a similar organelle, the apicoplast is an important potential target for development of anti-parasitic agents. Little is known about the biogenesis of this organelle, which is bounded by four membranes. Until now, only targeting to the apicoplast lumen has been explored. Such proteins are targeted courtesy of a signal sequence that allows entry into the secretory system and a transit peptide that routes them from the ER to the plastid. We have presented provocative evidence that the latter step occurs in a Golgi- independent manner. In the past grant period we identified two apicoplast membrane proteins (a transporter and a protease), both of which lack canonical targeting sequences. In contrast to luminal proteins, these proteins show cell cycle dependent localization to the apicoplast. Because of these differences as well as the distinct ultimate destinations, the routes and sequences that mediate targeting of non-luminal proteins likely involve novel elements. This proposal outlines experiments aimed at characterizing a set of proteins localized to various apicoplast compartments, and will dissect the mechanisms and sequences important for the proper localization of these proteins. We will also determine whether targeting of apicoplast membrane proteins is assisted by molecules known to be involved in ER exit processes or ER to Golgi trafficking. These studies will expand our understanding of the biogenesis of this unique organelle and provide additional information concerning its function.

Public Health Relevance

This project proposes to examine a plant-like organelle called the apicoplast in the parasite Toxoplasma gondii, an agent which causes encephalitis in immunocompromised individuals and birth defects when acquired during pregnancy. As humans lack an apicoplast, it provides a potential target for new interventions against the parasite.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050506-08
Application #
7795244
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Rogers, Martin J
Project Start
2001-08-01
Project End
2013-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
8
Fiscal Year
2010
Total Cost
$472,725
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109
Biddau, Marco; Bouchut, Anne; Major, Jack et al. (2018) Two essential Thioredoxins mediate apicoplast biogenesis, protein import, and gene expression in Toxoplasma gondii. PLoS Pathog 14:e1006836
Bouchut, Anne; Geiger, Jennifer A; DeRocher, Amy E et al. (2014) Vesicles bearing Toxoplasma apicoplast membrane proteins persist following loss of the relict plastid or Golgi body disruption. PLoS One 9:e112096
DeRocher, Amy E; Karnataki, Anuradha; Vaney, Pashmi et al. (2012) Apicoplast targeting of a Toxoplasma gondii transmembrane protein requires a cytosolic tyrosine-based motif. Traffic 13:694-704
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Ojo, Kayode K; Larson, Eric T; Keyloun, Katelyn R et al. (2010) Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors. Nat Struct Mol Biol 17:602-7
Hernandez, Jeniffer B; Newton, Ryan H; Walsh, Craig M (2010) Life and death in the thymus--cell death signaling during T cell development. Curr Opin Cell Biol 22:865-71

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