PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis
PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis
复制标题
PKCβII 磷酸化 ACSL4 放大脂质过氧化诱导铁死亡
DOI：
10.1038/s41556-021-00818-3
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发表时间：
2022-01-13
影响因子：
21.3
通讯作者：
Zhu, Xiao-Feng
中科院分区：
文献类型：
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作者：
Zhang, Hai-Liang;Hu, Bing-Xin;Zhu, Xiao-Feng
脂质过氧化物的积累被认为是铁凋亡发生的决定因素。然而，与铁凋亡相关的脂质过氧化反应的传感器和放大过程仍然不清楚。在这里，我们通过独立的全基因组CRISPR-Cas9和激酶抑制剂文库筛选将PKC β II确定为铁凋亡的关键贡献者。我们的研究结果表明，PKC β II传感器的初始脂质过氧化物和放大脂质过氧化与铁通过磷酸化和激活ACSL 4。脂质组学分析表明，活化的ACSL 4催化含多不饱和脂肪酸的脂质生物合成，促进脂质过氧化产物的积累，导致铁凋亡。PKC β II-ACSL 4通路的减弱在体外有效阻断铁凋亡，并在体内损害铁凋亡相关的癌症免疫治疗。我们的研究结果确定了PKC β II作为脂质过氧化的传感器，脂质过氧化-PKC β II-ACSL 4正反馈轴可能为铁中毒相关疾病的治疗提供潜在的靶点。通过CRISPR-Cas9和激酶抑制剂筛选，Zhang等人显示PKC β II磷酸化并激活ACSL 4以增强含多不饱和脂肪酸的脂质生物合成，从而促进脂质过氧化和铁凋亡的积累。
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 PKC beta II as a critical contributor of ferroptosis through independent genome-wide CRISPR-Cas9 and kinase inhibitor library screening. Our results show that PKC beta II 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 PKC beta II-ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKC beta II as a sensor of lipid peroxidation, and the lipid peroxidation-PKC beta II-ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment.Through CRISPR-Cas9 and kinase inhibitor screening, Zhang et al. show that PKC beta II phosphorylates and activates ACSL4 to enhance polyunsaturated fatty acid-containing lipid biosynthesis, thereby promoting accumulation of lipid peroxidation and ferroptosis.