Srebp-controlled glucose metabolism is essential for NK cell functional responses

Abstract

Activated natural killer (NK) cells engage in a robust metabolic response that is required for normal effector function. Using genetic, pharmacological and metabolic analyses, we demonstrated an essential role for Srebp transcription factors in cytokine-induced metabolic reprogramming of NK cells that was independent of their conventional role in the control of lipid synthesis. Srebp was required for elevated glycolysis and oxidative phosphorylation and promoted a distinct metabolic pathway configuration in which glucose was metabolized to cytosolic citrate via the citrate–malate shuttle. Preventing the activation of Srebp or direct inhibition of the citrate–malate shuttle inhibited production of interferon-γ and NK cell cytotoxicity. Thus, Srebp controls glucose metabolism in NK cells, and this Srebp-dependent regulation is critical for NK cell effector function.

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Figure 1: Srebp transcription factors are required for cytokine-induced NK cell growth and proliferation.
Figure 2: Srebp transcription factors are required for cytokine-induced glycolysis and OxPhos.
Figure 3: Inhibition of Srebp does not prevent mTORC1 signaling.
Figure 4: Glucose is metabolized to cytosolic citrate in cytokine activated NK cells.
Figure 5: Cytosolic citrate metabolism is needed to sustain elevated OxPhos and glycolysis.
Figure 6: The Srebp-controlled citrate–malate shuttle is required for NK cell effector function.
Figure 7: Srebp activity is important for therapeutic NK cell anti-tumor responses in vivo.

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Acknowledgements

We thank the Comparative Medicine Unit, Trinity College Dublin for use of their facilities. Supported by Science Foundation Ireland (12/IP/1286 and 13/CDA/2161 for the D.K.F. laboratory); Irish Cancer Society (research scholarship CRS15OBR to K.L.O'B. which includes support from the Children's Leukaemia Research Project), Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil (research scholarship BEX 13446134 to V.Z.B.) and Deutsche Forschungsgemeinschaft (KFO-262 for K.D.).

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Contributions

Conceptualization, N.A., R.P.D. and D.K.F.; methodology, N.A., R.P.D., L.D., V.Z.-B., C.M.G., K.D. and D.K.F.; investigation, N.A., K.L.O'B. R.P.D., L.D., V.Z.-B., R.M.L., K.D. and P.H.; writing (original draft), N.A. and D.K.F.; writing (review and editing), N.A., K.L.O'B., P.J.O., C.M.G. and D.K.F.; and supervision, P.J.O., L.L., C.M.G. and D.K.F.

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Correspondence to David K Finlay.

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Integrated supplementary information

Supplementary Figure 1 Srebp transcription factors are activated in NK cells stimulated with IL-2 plus IL-12.

(a) Schematic figure of Srebp activation and processing. Srebp is synthesized as an integral membrane protein within the Endoplasmic Reticulum (ER). Following translocation of Srebp along with Scap to the Golgi (←) two protease cleavage events release the active Srebp transcription factor, which then enters the nucleus (↑) and binds to Sterol regulatory element (SRE) containing promoters. 25HC inhibits Srebp activation by promoting the interaction of Scap with Insig, an ER anchor protein, thus preventing Srebp translocation to the Golgi. PF429242 inhibits site 1 protease (S1P) preventing Srebp processing. Deletion of Scap inhibits Srebp activation by preventing Srebp translocation to the Golgi. (b) Quantitative RT-PCR analysis of Fasn, Scd1, Hmgcs1 and Acat2 mRNA in NK cells left unstimulated or stimulated for 18 h with IL-2 + IL-12 +/- PF429242. (c) Analysis of the expression of Fasn, Hmgcs1 and Acat2 mRNA in NK cells stimulated for 18 h with IL-2 + IL-12 +/- rapamycin by qRT-PCR. (d) Gating strategy for the analysis of murine NK cells. Data shown is mean +/- S.E.M of 3-6 experiments. mRNA values shown are relative to IL-2 + IL-12 stimulated NK cells. * P<0.05, ** P <0.01, *** P <0.001, **** P <0.0001. (1-sample t-test).

Supplementary Figure 2 Srebp transcription factors are required for cytokine induced growth and proliferation of NK cells.

(a-c) CFSE-stained NK cells were left unstimulated or stimulated with IL-2 + IL-12 +/- PF429242 (a,b) or +/- C75 (b,c) for 24-48 h and analyzed by flow cytometry for FSC-A and CFSE-dilution, as indicated. (b) Quantitative analysis of proliferated NK cells after 48 h of NK cell stimulation with IL-2 + IL-12 +/- the inhibitors 25HC, PF429242, TOFA or C75. Statistical analysis relative to IL-2 + IL-12 stimulated NK cells is shown on the graph with other statistical comparisons summarized in the table below. (d) Viability analysis of NK cells stimulated with IL-2 + IL-12 for 20 h +/- 25HC, PF429242 or TOFA. (e,f) IL2-induced proliferation of cytotoxic T lymphocytes (CTL) was measured as the increase in cell number after 48 h +/- PF429242, 25HC (e) or TOFA (f). The dashed line indicates the density at which the cells were seeded. Data shown are representative of 5 experiments (a,c) or mean +/- S.E.M of 4 (e,f) or 5 (b,d) experiments. *P <0.05, ** P <0.01, **** P <0.0001. (One-way ANOVA with Tukey post-test (b,d,e); paired two-tailed t-test (f)).

Supplementary Figure 3 Calculations made from Seahorse traces.

(a) Calculation of (top) glycolytic reserve, glycolytic capacity and basal rate of glycolysis from extracellular acidification rate (ECAR) trace, and (bottom) spare respiratory capacity (SRC), maximal respiration and rate of basal oxidative phosphorylation (OxPhos) from oxygen consumption rate (OCR) trace. (b,c) Basal glycolysis (b) and glycolytic capacity (c) were calculated for NK cells stimulated for 18 h with IL-2 + IL-12 +/- TOFA or C75. Values are relative to NK cells stimulated in the absence of inhibitors. (d) ScapKO (Scapflox/flox x Tamox-Cre) or ScapWT (ScapWT/WT x Tamox-Cre) NK cells were analyzed by qRT-PCR for the expression of Scap, Fasn, Hmgcs1 and Acat2 mRNA. Values shown are relative to ScapWT NK cells. (e) Quantitative analysis of proliferated ScapKO and ScapWT NK cells stimulated for 48 h with IL-2 + IL-12. Data shown is mean +/- S.E.M of 3-4 experiments. *P <0.05, ** P <0.01. (Paired two-tailed t-test (e); one-sample t-test (b-d)).

Supplementary Figure 4 Srebp transcription factors are required for cytokine induced glycolysis and OxPhos.

(a) Quantitative RT-PCR analysis of G6pd mRNA in unstimulated NK cells or IL-2 + IL-12 stimulated NK cells treated for 18 h with or without the inhibitors 25HC or PF429242. Values shown are relative to IL-2 + IL-12 stimulated NK cells. (b) Schematic figure of 1,2-13C2-glucose flux through glycolysis and pentose phosphate pathway. Filled circles indicate 13C-labeled carbon. Data shown is mean +/- S.E.M of 3 experiments. (One-way ANOVA with Tukey post-test).

Supplementary Figure 5 Glucose is metabolized to cytosolic citrate in cytokine activated NK cells.

(a) Analysis of isotopologue distribution of citrate in NK cells stimulated +/- IL-2 + IL-12 for 18 h in media containing 13C6-glucose. (b) Schematic figure of isotopologue distribution of citrate, succinate and fumarate in the case where the majority of citrate is exported to the cytosol (left) or where citrate progresses through the TCA cycle (right). (c) NK cells were stimulated for 18 h with IL-2 + IL-12 and then extracellular acidification rates (ECAR) were calculated at the second measurement after the addition of SB204990 or vehicle control. (d,e) IL2-maintained cytotoxic T lymphocytes (CTL) were analyzed for ECAR values at the second measurement following injection of BMS303141 (d), SB204990 (e) or vehicle control (DMSO). (f) Analysis of fold increase in ECAR values at the second measurement after injection of SB204990 to 18 h with IL-2 + IL-12-stimulated NK cells or IL2-cultured CTLs relative to DMSO control. Data shown is mean +/- S.E.M of 4 (d), 4-5 (f), 5 (c,e) or 6 (a) independent experiments. ns, non-significant, * P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001. (Two-way ANOVA with Sidak post-test (a); paired (c,d,e) or unpaired (f) two-tailed t-test).

Supplementary Figure 6 The Srebp-controlled citrate–malate shuttle is required for NK cell effector function.

(a,b) NK cells were stimulated for 20 h with IL-2 + IL-12 in the presence or absence of TOFA or C75 and IFNγ production (a) and granzyme B (b) expression analyzed by flow cytometry. (c) Gating strategy for the analysis of human NK cells (d-g) Human NK cells were stimulated with IL-12 + IL-15 for 18 h +/- 25HC or PF249242 and IFNγ production (d,e) and granzyme B (f,g) expression analyzed by flow cytometry. Shown is MFI of IFN-γ positive NK cells (d-e). Data shown is mean +/- S.E.M of 4 (a,b), 7 (d), 8 (f) or 9 (e,g) experiments. * P<0.05, ns, non-significant. (One-way ANOVA with Tukey post-test (a,b); paired two-tailed t-test (d-g)).

Supplementary Figure 7 The Srebp dependent citrate–malate shuttle.

Glycolysis-derived pyruvate is typically considered to promote mitochondrial oxidative phosphorylation (OxPhos) through fuelling the tricarboxylic acid (TCA) cycle (left). The TCA cycle feeds electrons into the electron transport chain via NADH and FADH2 reducing equivalents. Herein, this study demonstrates that cytokine activated NK cells adopt a distinct metabolic configuration called the citrate-malate shuttle (CMS)(right). Pyruvate is metabolized to acetyl-CoA, which is used with oxaloacetate (OAA) to generate citrate. This mitochondrial citrate is then exported into the cytoplasm through the citrate-malate antiporter (Slc25a1). Slc25a1 is an obligate antiporter and so to sustain citrate export, malate must be imported into the mitochondria. In the cytoplasm, citrate is cleaved by ATP citrate lyase (ACLY) into acetyl-CoA and OAA. OAA is further metabolized to generate malate to be imported into the mitochondria, where it is converted back to OAA, thus completing the cycle. The net outputs of the CMS are (1) the import of electrons from NADH in the cytoplasm to generate mitochondrial NADH to fuel OxPhos, (2) the regeneration of NAD+ in the cytoplasm, an essential cofactor for GAPDH and therefore glycolysis, and (3) the generation of cytoplasmic acetyl-CoA, which is important for acetylation reactions and fatty acid synthesis. Cytokine activated NK cells primarily use the CMS, and not the TCA cycle, to drive OxPhos. Srebp transcription factors control the expression of the two key components of the CMS, Slc25a1 and ACLY.

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Assmann, N., O'Brien, K., Donnelly, R. et al. Srebp-controlled glucose metabolism is essential for NK cell functional responses. Nat Immunol 18, 1197–1206 (2017). https://doi.org/10.1038/ni.3838

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