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PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis

Nature Cell Biology volume 24, pages 88–98 (2022)Cite this article

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Abstract

The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain obscure. Here we identify PKCβII as a critical contributor of ferroptosis through independent genome-wide CRISPR–Cas9 and kinase inhibitor library screening. Our results show that PKCβII senses the initial lipid peroxides and amplifies lipid peroxidation linked to ferroptosis through phosphorylation and activation of ACSL4. Lipidomics analysis shows that activated ACSL4 catalyses polyunsaturated fatty acid-containing lipid biosynthesis and promotes the accumulation of lipid peroxidation products, leading to ferroptosis. Attenuation of the PKCβII–ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKCβII as a sensor of lipid peroxidation, and the lipid peroxidation–PKCβII–ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment.

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Fig. 1: Identification of PKCβII as a critical contributor of ferroptosis.
Fig. 2: Identification of PKCβII as a biomarker of ferroptosis.
Fig. 3: PKCβII activation is essential for ferroptosis.
Fig. 4: PKCβII interacts with and directly phosphorylates ACSL4.
Fig. 5: Phosphorylation of Thr328 is critical for the activation and pro-ferroptotic functions of ACSL4.
Fig. 6: Attenuation of the PKCβII–ACSL4 pathway reduces the efficacy of immunotherapy by suppressing ferroptosis.
Fig. 7: Proposed model for PKCβII phosphorylation of ACSL4 to amplify lipid peroxidation for ferroptosis.

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Data availability

Previously published data from 49 patients with melanoma who underwent tumour biopsies before starting immunotherapy that were re-analysed here are available at the Gene Expression Omnibus under the accession code GSE91061 (ref. 28). Data of the CRISPR screening are available as Supplementary Table 1. Data of the kinase screening are available as Supplementary Table 2. Lipidomics data are available as Supplementary Tables 3 and 4. All other data supporting the findings of this study are available from the corresponding author on reasonable request. Source data are provided with this paper.

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Acknowledgements

This study was supported by the Natural Science Foundation of China (grant nos 81630079 (to X.-F.Z.), 81803006 (to H.-L.Z.), 81772624 (to R.D.), 81972855 (to X.-F.Z.) and 82173092 (to R.D.)), Natural Science Foundation of Guangdong Province (grant no. 2021A1515010092 to R.D.), National Postdoctoral Program for Innovative Talents (grant no. BX2021391 to Z.-L.L.), China Postdoctoral Science Foundation (grant no. 2020M683107 to T.D.). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

    Hai-Liang Zhang, Bing-Xin Hu, Zhi-Ling Li, Tian Du, Jia-Lu Shan, Zhi-Peng Ye, Xiao-Dan Peng, Xuan Li, Yun Huang, Xian-Ying Zhu, Yu-Hong Chen, Gong-Kan Feng, Dajun Yang, Rong Deng & Xiao-Feng Zhu

  2. Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China

    Tian Du

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Contributions

X.-F.Z. and H.-L.Z. conceived the idea. H.-L.Z. and B.-X.H. performed most experiments. Z.-L.L., Z.-P.Y., X.-D.P. and G.-K.F. performed the animal experiments. X.L., X.-Y.Z. and Y.-H.C. performed the lipidomic analyses. Y.H. and T.D. analysed the clinical data. H.-L.Z., R.D. and X.-F.Z. wrote the manuscript. All co-authors have seen and approved the manuscript.

Corresponding authors

Correspondence to Rong Deng or Xiao-Feng Zhu.

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Nature Cell Biology thanks Marcus Conrad and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 PKC kinase inhibitors inhibit ferroptosis.

(a) An immunoblot showing the levels of PKCα phosphorylation in MDA-MB-231 or HT1080 cells subjected to the indicated treatments for 16 h. p-PKCα, phospho-PKCα. The experiment was repeated three times, independently, with similar results. (b,c) Cell death (left) and lipid peroxidation (right) measurements in HT1080 cells subjected to the indicated treatments for 20 h. Erastin, 4 μM; RSL3, 50 nM; Go6983, 5 μM; Enza, 5 μM enzastaurin. (d,e) Cell death (left) and lipid peroxidation (right) measurements in MEF cells subjected to the indicated treatments for 16 h. Erastin, 2 μM; RSL3, 25 nM; Go6983, 5 μM; Enza, 5 μM enzastaurin. (f) Analysis of radical trapping/antioxidant potential of Go6983 and enzastaurin (Enza) compared to α-tocopherol. Antioxidant activity was assessed using the DPPH assay. Absorption was measured at 517 nm. (g) Representative co-autoxidations of STY-BODIPY (1 μM)-embedded liposomes of egg PC (5 mM) initiated by di-tert-undecyl hyponitrite (0.2 mM, black) and inhibited by either Go6983 (20 μM, red), enzastaurin (20 μM, blue), or α-tocopherol (20 μM, green). (h) Cell death (left) and lipid peroxidation (right) measurements in the indicated cells treated with 5 μM erastin or 2.5 μM RLS3 for 20 h. The mean ± s.d. of n = 3 independent experiments are shown. Statistical analysis was performed using an unpaired two-tailed t test.

Source data

Extended Data Fig. 2 PKCβII promote ferroptosis.

(a-l) Cell viability measurements in MDA-MB-231 and HT1080 cells subjected to the indicated treatments. Error bars are mean ± s.d., n = 3 independent repeats. Statistical analysis was performed using a two-way ANOVA analysis.

Source data

Extended Data Fig. 3 PKCβII has a direct impact on ferroptosis sensitivity.

An immunoblot showing the expression of PKCβII in HS578T (a), MDA-MB-468 (g), MCF7 (m) and BT474 (s) cells subjected to the indicated treatments. Data in a, g, m, s are representative of n = 3 biologically independent experiments. (b-e, h-k, n-q, t-w) Cell viability measurements in cells subjected to the indicated treatments. (f, l, r, x) Lipid peroxidation measurements in the indicated cells subjected to the indicated treatments for 20 h. f and l, Erastin, 10 μM; RSL3, 6 μM, Time, 24 h. r and x, Erastin, 15 μM; RSL3, 6 μM, Time, 24 h. b-e, h-k, n-q, t-w, error bars are mean ± s.d., n = 3 independent repeats. Statistical analysis was performed using a two-way ANOVA analysis. f, l, r, x, the mean ± s.d. of n = 3 independent experiments are shown. Statistical analysis was performed using an unpaired two-tailed t test.

Source data

Extended Data Fig. 4 PKCβII activation is essential for ferroptosis.

(a-b) Cell death measurements in MDA-MB-231 (a) and HT1080 (b) cells subjected to the indicated treatments. (c) An immunoblot showing the expression of membrane-PKCα, βI, γ, δ, ζ in MDA-MB-231 cells treated with erastin at the indicated concentration for 16 h. (d) Lipid peroxidation measurement in the indicated MDA-MB-231 cells or HT1080 cells treated with erastin or RLS3 for 20 h. For MDA-MB-231 cells, erastin, 5 μM; RSL3, 2.5 μM. For HT1080 cells, erastin, 4 μM; RSL3, 50 nM. The mean ± s.d. of n = 3 independent experiments are shown. Statistical analysis was performed using an unpaired two-tailed t test. (e,f) An immunoblot showing the expression of membrane-PKCβII in MDA-MB-231 (e) or HT1080 cells (f) subjected to the indicated treatments for 16 h. For MDA-MB-231 cells, erastin, 5 μM; RSL3, 2.5 μM. For HT1080 cells, erastin, 4 μM; RSL3, 50 nM. (g,h) Endogenous PKCβII was immunoprecipitated from MDA-MB-231 (g) and HT1080 (h) cells subjected to the indicated treatments for 16 h, followed by immunoblotting using a phospho-Ser/Thr antibody. For MDA-MB-231 cells, erastin, 5 μM; RSL3, 2.5 μM. For HT1080 cells, erastin, 4 μM; RSL3, 50 nM. a, b, d, the mean ± s.d. of n = 3 independent experiments are shown. Statistical analysis was performed using an unpaired two-tailed t test. Data in c, e-h, are representative of n = 3 biologically independent experiments.

Source data

Extended Data Fig. 5 PKCβII did not affect the protein level of GPX4 or cellular divalent iron levels.

(a) An immunoblot showing the expression of GPX4 in MDA-MB-231 cells subjected to the indicated treatments for 18 h. (b) Cellular divalent iron levels were assayed in the indicated MDA-MB-231 cells. (c) Cellular divalent iron levels were assayed in MDA-MB-231 cells subjected to the indicated treatments. Go6983, 5 μM; Enza, 5 μM. (d) The potential phosphorylation sites of ACSL4 predicted by GPS and the SCANSITE program. (e) An immunoblot showing the levels of ACSL4 in the indicated cells. (f-i) Endogenous ACSL4 was immunoprecipitated from cells subjected to the indicated treatments for 16 h, followed by immunoblotting using an ACSL4 phospho-T328 antibody. For MDA-MB-231 cells, erastin, 5 μM; RSL3, 2.5 μM. For HT1080 cells, erastin, 4 μM; RSL3, 50 nM. b, c, the mean±s.d. of n = 3 independent experiments are shown. Statistical analysis was performed using an unpaired two-tailed t test. Data in a, e-i, are representative of n = 3 biologically independent experiments.

Source data

Extended Data Fig. 6 Fer-1 or Lipro-1 blocks PKCβII–ACSL4 pathway through eliminating lipid peroxides.

(a) MDA-MB-231 and HT1080 cells were cotransfected with the FLAG-ACSL4 plasmid and HA-ACSL4 plasmid. Then, these cells were subjected to the indicated treatments for 16 h, and FLAG-ACSL4 was immunoprecipitated and immunoblotted using an HA antibody. For MDA-MB-231 cells, erastin, 5 μM; RSL3, 2.5 μM; Fer-1, 5 μM; Lipro-1, 5 μM. For HT1080 cells, erastin, 4 μM; RSL3, 50 nM; Fer-1, 5 μM; Lipro-1, 5 μM. (b) MDA-MB-231 and HT1080 cells subjected to the indicated treatments for 16 h. Cell lysates were immunoblotted under non-reducing conditions. For MDA-MB-231 cells, erastin, 5 μM; RSL3, 2.5 μM; Fer-1, 5 μM; Lipro-1, 5 μM. For HT1080 cells, erastin, 4 μM; RSL3, 50 nM; Fer-1, 5 μM; Lipro-1, 5 μM. Data in a,b are representative of n = 3 biologically independent experiments. (c) The relative signal intensity of PE species containing mono-unsaturated and saturated fatty acids in cells were subjected to the indicated treatments for 16 h. Erastin, 5 μM; Enza, 5 μM. Data show the mean±s.d. of n = 6 independent experiments. Statistical analysis was performed using unpaired two-tailed t tests.

Source data

Extended Data Fig. 7 T328 phosphorylation is critical for the pro-ferroptotic functions of ACSL4.

Vector control, ACSL4-WT, ACSL4-T328A or ACSL4-T328D plasmids were transfected into ACSL4-knockout MDA-MB-231 and HT1080 cells. An immunoblot showing the levels of ACSL4 in the indicated cells. Data are representative of n = 3 biologically independent experiments. (b,c) Cell death (b) or lipid peroxidation (c) measurements in the indicated cells treated with 4 μM erastin or 50 nM RSL3 for 20 h. The P values correspond to the comparison between the ACSL4-T328A and matched ACSL4-WT cells under erastin or RSL3 treatment. The mean±s.d. n = 3 of independent experiments are shown. Statistical analysis was performed using an unpaired two-tailed t test.

Source data

Extended Data Fig. 8 The ACSL4-T328D variant stably expressed in PKCβII knockout cells suffice to re-sensitize to ferroptosis.

(a, f) An immunoblot showing the expression of ACSL4 in MDA-MB-231 (a) and HT1080 (f) cells subjected to the indicated treatments. (b-e, g-j) Cell viability measurements in cells subjected to the indicated treatments. (k,l) Lipid peroxidation (k) and cell death (l) measurements in cardiomyocytes cells subjected to the indicated treatments. (m) Endogenous ACSL4 was immunoprecipitated from cardiomyocytes cells subjected to the indicated treatments, followed by immunoblotting using an ACSL4 phospho-T328 antibody. Data in a, f, m, are representative of n = 3 biologically independent experiments. b-e, g-j, error bars are mean±s.d., n = 3 independent repeats. Statistical analysis was performed using a two-way ANOVA analysis. K,l, the mean±s.d. of n = 3 independent experiments are shown. Statistical analysis was performed using an unpaired two-tailed t test.

Source data

Extended Data Fig. 9 PKCβII knockout reduces the efficacy of immunotherapy.

(a) Vector control, ACSL4-WT or ACSL4-T328A plasmids were transfected into ACSL4-knockout B16 cells. An immunoblot showing the levels of ACSL4 in the indicated cells. (b) PKCβ was knockout in 4T1 cells using CRISPER-Cas9 technology. An immunoblot showing the levels of PKCβII in the indicated cells. Data in a,b are representative of n = 3 biologically independent experiments. (c) Representative TIL dot plots from a representative mouse for each group are shown (left). The percentage of TILs for each group was calculated (right). The mean±s.d. are shown; n = 6 biologically independent mice. Statistical analysis was performed using an unpaired two-tailed t test.

Source data

Extended Data Fig. 10 PKCβII enhances the efficacy of immunotherapy by facilitating ferroptosis.

(a,b) Tumour growth of mouse B16-PKCβII-KO-Vector or B16-PKCβII-KO- PKCβII tumour xenografts in C57 mice following treatment with mouse anti-PD1 antibody or lipoxstatin alone or in combination. (n = 6 mice per group). Tumour volumes (a) and tumour weights (b) upon autopsy on day 15 were calculated. (c) Relative lipid peroxidation in tumour cells isolated from B16-PKCβII-KO-Vector or B16-PKCβII-KO- PKCβII tumours. (d-g) The percentage of TILs for each group was calculated. The mean±s.d. are shown; n = 6 biologically independent mice. Statistical analysis was performed using an unpaired two-tailed t test.

Source data

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Supplementary Table 1

Supplementary Table 1. Data of the CRISPR screening. Supplementary Table 2. Data of the kinase screening. Supplementary Table 3. Lipidomic data 1. Supplementary Table 4. Lipidomic data 2. Supplementary Table 5. Correlation between ACSL4 and the immunotherapeutic response.

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Zhang, HL., Hu, BX., Li, ZL. et al. PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat Cell Biol 24, 88–98 (2022). https://doi.org/10.1038/s41556-021-00818-3

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