Sterol Regulatory Element Binding Proteins; Central Metabolic Regulators of Natural Killer Cells
Citation:
O'BRIEN, KATIE, Sterol Regulatory Element Binding Proteins; Central Metabolic Regulators of Natural Killer Cells, Trinity College Dublin.School of Biochemistry & Immunology, 2020Download Item:
Abstract:
Natural killer (NK) cells have important functions in the immune response against pathogen-
infected and transformed cells. NK cell metabolism is crucial for NK cell effector functions. In
this study sterol regulatory element binding protein (SREBP) transcription factors were
identified as a central regulator of NK cell metabolism and function. Through genetic and
pharmacological approaches, SREBP activity was shown to be essential for NK cell glycolysis
and oxidative phosphorylation in response to cytokine-stimulation with IL2 and IL12.
Furthermore, SREBP activity was identified as being essential for the functional responses of
NK cells ? both in vitro and in vivo. It was previously identified that NK cells utilise a specific
metabolic configuration known as the citrate-malate-shuttle (CMS) to support their
metabolism and function. SREBP controls expression of two key components of the CMS -
the enzyme ATP citrate lyase and the antiporter, SLC25A1. However, it was considered that
SREBP may be controlling other aspects of NK cell metabolism. Indeed, it was identified that
SREBP activity is required for optimal polyamine biosynthesis in IL2/IL12-stimulated NK
cells. Further investigation involving the pharmacological inhibition of polyamine synthesis ,
identified that polyamines were required for NK cell metabolism and function and that
hypusination - a polyamine-dependent post-translational modification, was crucial for the
ability of NK cells to upregulate oxidative phosphorylation levels in response to stimulation.
Exploration of the mechanism linking SREBP activity to polyamine synthesis revealed that
SREBP activity is required for the upregulation of cMYC expression in response to IL2/IL12 in
NK cells. cMYC is well documented to have a role in the control of the de novo polyamine
synthesis pathway. Therefore, this work has identified a crucial role for SREBP transcription
factors in the control of NK cell metabolic and functional responses.
Sponsor
Grant Number
Irish Cancer Society
Author's Homepage:
https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:KOBRIEN3Description:
APPROVED
Author: O'BRIEN, KATIE
Advisor:
Finlay, DavidQualification name:
Doctor of Philosophy (Ph.D.)Publisher:
Trinity College Dublin. School of Biochemistry & Immunology. Discipline of BiochemistryType of material:
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Full text availableKeywords:
SREBP, NK cell, Metabolism, Polyamines, ImmunometabolismMetadata
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