Uncovering molecular innovation in the malaria plastid organelle through forward genetics
Abstract/Contents
- Abstract
- Plasmodium parasites and related apicomplexans are important human pathogens with major global burdens. These parasites represent a highly divergent and understudied branch of eukaryotes, and as such often defy the expectations set by model organisms. One striking example of unique apicomplexan biology is the apicoplast, an essential but non-photosynthetic plastid derived from a secondary (eukaryote-eukaryote) endosymbiosis. Endosymbioses are a major driver of molecular and cellular innovation, and biogenesis of the four-membrane apicoplast poses a unique challenge requiring evolution of new machinery. As such, apicoplast biogenesis pathways represent a hot spot for cellular innovation, yet few molecular players have been identified. To discover organellar pathways with evolutionary and biomedical significance, we conducted a mutagenesis screen for essential apicoplast biogenesis genes in P. falciparum using a novel fluorescent reporter and a chemical rescue that permits conditional disruption of the apicoplast. We identified fourteen gene candidates, and validated that six are specifically essential for apicoplast biogenesis. Three validated genes had no previous functional annotation, including a triosephosphate isomerase (TIM)-barrel which we show is derived from a core metabolic enzyme but evolved a new activity for its role in apicoplast biogenesis. We also validate a CaaX protease and bacteriocin processing (CPBP) gene, which based on gene annotations was expected to function as a CaaX protease in the eukaryotic post-prenylation processing pathway. However, we unexpectedly find that it does not act as a eukaryotic CaaX protease, but is instead derived from a cyanobacterial gene and likely performs a conserved chloroplast function that has been retained for complex plastid biogenesis. Altogether, our screen identified both unknown and unexpected genes, highlighting the abundance of molecular innovation in apicoplast biogenesis pathways. Furthermore, this proof-of-concept screen enables future expansion to a genome-scale screen, allowing broad discovery of these unique and essential pathways.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Meister, Thomas |
|---|---|
| Degree supervisor | Yeh, Ellen |
| Thesis advisor | Yeh, Ellen |
| Thesis advisor | Boothroyd, John C |
| Thesis advisor | Krasnow, Mark, 1956- |
| Thesis advisor | Maduke, Merritt C, 1966- |
| Degree committee member | Boothroyd, John C |
| Degree committee member | Krasnow, Mark, 1956- |
| Degree committee member | Maduke, Merritt C, 1966- |
| Associated with | Stanford University, Department of Molecular and Cell Physiology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Thomas Richard Meister. |
|---|---|
| Note | Submitted to the Department of Molecular and Cell Physiology. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/gv265vn3499 |
Access conditions
- Copyright
- © 2021 by Thomas Meister
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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