De novo polyamine synthesis supports metabolic and functional responses in activated murine NK cells

Cellular metabolism is dynamically regulated in NK cells and strongly influences their responses. Metabolic dysfunction is linked to defective NK cell responses in diseases such as obesity and cancer. The transcription factors, sterol regulatory element binding protein (SREBP) and cMyc, are crucial for controlling NK cell metabolic and functional responses, though the mechanisms involved are not fully understood. This study reveals a new role for SREBP in NK cells in supporting de novo polyamine synthesis through facilitating elevated cMyc expression. Polyamines have diverse roles and their de novo synthesis is required for NK cell glycolytic and oxidative metabolism and to support optimal NK cell effector functions. When NK cells with impaired SREBP activity were supplemented with exogenous polyamines, NK cell metabolic defects were not rescued but these NK cells displayed significant improvement in some effector functions. One role for polyamines is in the control of protein translation where spermidine supports the posttranslational hypusination of translation factor eIF5a. Pharmacological inhibition of hypusination also impacts upon NK cell metabolism and effector function. Considering recent evidence that cholesterol‐rich tumor microenvironments inhibit SREBP activation and drive lymphocyte dysfunction, this study provides key mechanistic insight into this tumor‐evasion strategy. Cytokine‐stimulation of NK cells drives signaling through SREBP and cMyc transcription factors that promotes increased flux through glucose and polyamine metabolic pathways. These metabolic fluxes are crucial for optimal NK cell effector responses via multiple mechanisms including polyamine‐dependent hypusination. 25‐Hydroxycholesterol (25HC)‐mediated inhibition of SREBP impairs cMyc expression and polyamine synthesis.