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

Abstract

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.

Metabolic Dynamics of In Vitro CD8+ T Cell Activation

“…Notably, central carbon metabolism, tricarboxylic acid (TCA) cycle, and amino acid metabolism are among the top-scoring pathways. This is in line with previous findings that found similar pathways enriched in metabolic differences by 13 C tracing [11], even though the initial annotation of FIA features is based on exact mass only. Two of the major metabolic effects during the activation of CD8+ T cells that have been described previously are the increase in glycolytic lactate production and the decrease in fatty acid oxidation (FAO) in activated cells compared to naïve CD8+ T cells [11,12].…”

“…Recently, the importance of polyamines was described for several immune cell types. Polyamines were described to accumulate in NK cells and in CD4+ T cells following activation from naïve state [13,14] and this accumulation was shown to be required for appropriate effector function. In IL4 activated macrophages, blocking of polyamine biosynthesis blunted their activation [15].…”

Arginine-dependent hypusination of the eukaryotic translation initiation factor (eIF)5A drives erythroid lineage differentiation

“…eIF5A is also important in regulating host-pathogen interactions from both sides; augmented hypusine synthesis increases the virulence of Fusarium graminearum , a devastating fungal pathogen of cereals (Martinez-Rocha et al, 2016) and the Helicobacter pylori / Citrobacter rodentium -induced synthesis of hypusine in macrophages is required for their optimal anti-microbial responses (Martinez-Rocha et al, 2016). Indeed, within immune cell lineages, hypusination has been found to control the differentiation and function of B cells, macrophages, NK cells, and T cells (Alsaleh et al, 2020; O’Brien et al, 2021; Puleston et al, 2021; Puleston et al, 2019; Zhang et al, 2019a).…”

Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses

“…It is evident that polyamines and hypusine also promote the proper function of other immune cells, such as NK cells. Pharmacological modulation of polyamine biosynthesis via DFMO or N 1 ,N 11 -diethylnorspermine (DENSpm) reduced NK cell proliferation as well as IFNγ and granzyme B production in vitro [26]. Moreover, inhibition of hypusination via GC7 similarly reduced IFNγ and granzyme B production as well as cytotoxicity, without affecting viability.…”

“…Moreover, inhibition of hypusination via GC7 similarly reduced IFNγ and granzyme B production as well as cytotoxicity, without affecting viability. Thus, decreased polyamines, especially spermidine, are detrimental to NK cell function in vitro [26], bringing to question the effects of systemic polyamine depletion strategies in disease settings such as cancer.…”