Role of leishmanial glyceraldehyde3-phosphate dehydrogenase in host-parasite interaction
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Role of leishmanial glyceraldehyde3-phosphate dehydrogenase in
host-parasite interaction
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| Creator |
DAS, PRIYA
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| Subject |
Structural Biology & Bioinformatics
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| Description |
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classic glycolytic enzyme and
is involved in the reversible oxidative phosphorylation of glyceraldehyde-3-phosphate in
the presence of inorganic phosphate and nicotinamide adenine dinucleotide (NAD).
However, emerging evidence indicates that GAPDH is a multifunctional protein
implicated in diverse functions independent of its role in energy metabolism; GAPDH
participates in numerous cellular functions, in addition to glycolytic effects, contributes
to nuclear tRNA export, DNA replication and repair, endocytosis, exocytosis,
cytoskeletal organization, iron metabolism, carcinogenesis, and cell death. It also acts as
an mRNA-binding protein, controlling posttranscriptional gene regulation.
In the case of Leishmania, apart from glycolysis, no other function of GAPDH is known.
Specific post-translational modifications, protein-protein interactions, and subsequent
changes in the intracellular distribution of GAPDH in leishmanial species remain
unknown. Considering all these facts together, we tried to find out the role of GAPDH in
Leishmania other than its role in glycolysis. To understand the non-glycolytic function of
LmGAPDH, we have generated control (CT), overexpressed (OE), half-knockout (HKO)
and complement (CM) cell lines. HKO cells exhibited reduced virulence compared to
control cells when infected with macrophages and BALB/c mice, showing that
LmGAPDH plays an important role in Leishmania infection and disease progression. We
have demonstrated that LmGAPDH is localized within the extracellular vesicles (EVs)
released by Leishmania during infection and, by different molecular biology techniques,
established that EV mediated LmGAPDH suppresses the production of pro-inflammatory
cytokines like Tumor Necrosis Factor α (TNF-α), which seems to have a primordial role
in the process of controlling infection. In vitro protein translation and mRNA binding
assays indicate that LmGAPDH binding to the AU-rich 3'-UTR region of TNF-α mRNA
is the primary cause for the limitation of its production. Together, these findings confirm
that the LmGAPDH found in EVs inhibits TNF-α expression in macrophages via posttranscriptional repression during infection. So, in this project, we attempted to uncover a
novel mechanism by which the Leishmania parasite suppresses host immune response,
which is critical for developing new drugs and therapeutic strategies against the disease.
Here we have illustrated our research in three separate chapters; Chapter1 elucidate
mainly the cloning, expression and localization of LmGAPDH from Leishmania major.
Chapter2 deals with the functional characterization of LmGAPDH contained within the
extracellular vesicles from Leishmania major and its essentiality in disease development
and progression. Chapter3 unravels a novel mechanism by which LmGAPDH contained
in the extracellular vesicles modulate host immune response through post-transcriptional
regulation of TNF-α expression.
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| Date |
2021
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| Type |
Thesis
NonPeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2832/1/Priya_Das_Thesis.pdf
DAS, PRIYA (2021) Role of leishmanial glyceraldehyde3-phosphate dehydrogenase in host-parasite interaction. PhD thesis, JADAVPUR UNIVERSITY. |
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| Relation |
http://www.eprints.iicb.res.in/2832/
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