Exploring the role of three deubiquitinases – UCH54, UCHL3 and USP7 – in the biology of the malaria parasite
dc.contributor.advisor
Philip, Nisha
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Young, Joanna
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Varma, Neelakshi
dc.date.accessioned
2024-11-18T13:52:30Z
dc.date.available
2024-11-18T13:52:30Z
dc.date.issued
2024-11-18
dc.description.abstract
Post-translational modification of proteins by ubiquitination serves as pivotal signals in the cell, exerting diverse effects ranging from degradation to modulating protein function, localization, and activity. Despite its fundamental role across eukaryotes, the involvement of ubiquitination in Plasmodium is poorly understood. Our project reveals key roles for three deubiquitinating enzymes in regulating the biology of the malaria parasite. Our data on PbUCHL3 and PbUCH54 reveal their role in the parasite's susceptibility to repeated artesunate exposure. These findings hold promise in combating artemisinin resistance, which is a growing cause for concern worldwide. Furthermore, our research highlights the indispensable role of PbUSP7 in malaria transmission biology. Within minutes of transmission to the mosquito vector, a sexual precursor male gametocyte replicates its DNA and differentiates to form eight flagellate male gametes. We have found an essential role for PbUSP7 in this process. USP7-deficient male gametocytes show aberrant nuclear characteristics and are unable to replicate their DNA in response to the mosquito environment. Whole-cell transcriptomic and proteomic data from USP7-knockout gametocytes reveal that the deubiquitinase alters the transcription as well as the stability of key proteins involved in DNA replication and flagella formation. Additionally, the deubiquitinase extensively regulates the stability of E3 ubiquitin ligases, key enzymes in the ubiquitin-proteasomal system that conjugate ubiquitin moieties to substrate cellular proteins. From stage-specific transcription to DNA replication and drug action, our studies on these three deubiquitinases unravel the complex biology of this age-old parasite while opening up new avenues for drug design and disease intervention.
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dc.identifier.uri
https://hdl.handle.net/1842/42662
dc.identifier.uri
http://dx.doi.org/10.7488/era/5356
dc.language.iso
en
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dc.publisher
The University of Edinburgh
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dc.subject
UCH54
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dc.subject
UCHL3
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dc.subject
USP7
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dc.subject
malaria parasite
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dc.subject
Post-translational modification
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dc.subject
ubiquitination
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dc.subject
Plasmodium
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dc.subject
deubiquitinating enzymes
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dc.subject
PbUCHL3
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dc.subject
PbUCH54
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dc.subject
PbUSP7
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dc.subject
malaria transmission biology
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dc.subject
USP7-knockout gametocytes
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dc.subject
deubiquitinase
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dc.title
Exploring the role of three deubiquitinases – UCH54, UCHL3 and USP7 – in the biology of the malaria parasite
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dc.type
Thesis or Dissertation
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dc.type.qualificationlevel
Doctoral
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dc.type.qualificationname
PhD Doctor of Philosophy
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