Sterol Regulatory Element Binding Proteins; Central Metabolic Regulators of Natural Killer Cells

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.