Targeting FAM134B-mediated reticulophagy activates sorafenib-induced ferroptosis in hepatocellular carcinoma.
Targeting FAM134B-mediated reticulophagy activates sorafenib-induced ferroptosis in hepatocellular carcinoma.
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DOI：
10.1016/j.bbrc.2021.12.019
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发表时间：
2021-12
影响因子：
3.1
通讯作者：
Zhiqian Liu;C. Ma;Qi Wang;Hao Yang;Zhihua Lu;Tao Bi;Zong-zhen Xu;Tao Li;Ling Zhang;Yajie Zhang;Jingfang Liu;Xiaoqing Wei;Jie Li
中科院分区：
文献类型：
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作者：
Zhiqian Liu;C. Ma;Qi Wang;Hao Yang;Zhihua Lu;Tao Bi;Zong-zhen Xu;Tao Li;Ling Zhang;Yajie Zhang;Jingfang Liu;Xiaoqing Wei;Jie Li
铁凋亡是一种与选择性自噬密切相关的细胞死亡，如铁蛋白自噬、脂肪自噬、时钟自噬和分子伴侣介导的自噬。然而，网状吞噬，特别是降解内质网（ER）片段（也称为ER-吞噬），在铁凋亡调控的作用仍然不清楚。在本研究中，我们发现索拉非尼（ferroptosis inducer）可以有效激活受体蛋白FAM 134 B介导的ER-吞噬，并且FAM 134 B敲低不仅阻断ER-吞噬，而且显著增强细胞对ferroptosis的敏感性，而不影响巨自噬。体内实验也得到了类似的结果。这些证据为铁凋亡的调控提供了新的线索。生物信息学分析结合RNA结合蛋白免疫沉淀和多聚核糖体分离初步表明PABPC 1可以与FAM 134 B mRNA相互作用并促进其翻译。综上所述，本研究揭示了PABPC 1-FAM 134 B-ER-phagy通路在铁凋亡中的作用，为新型抗癌策略提供了重要证据。
Ferroptosis is a kind of cell death closely related to selective autophagy, such as ferritinophagy, lipophagy, clockophagy and chaperone-mediated autophagy. However, the role of reticulophagy, which specifically degrades endoplasmic reticulum (ER) fragments (also known as ER-phagy), in ferroptosis regulation is still unclear. In this study, we found that sorafenib (ferroptosis inducer) can effectively activate the receptor protein FAM134B-mediated ER-phagy, and FAM134B knockdown not only blocked ER-phagy but also significantly strengthened cellular sensitivity to ferroptosis without affecting macroautophagy. In vivo experiments also yielded similar results. These evidences provided new clues for ferroptosis regulation. Subsequently, bioinformatic analysis combined with RNA binding protein immunoprecipitation and polyribosome fractionation preliminarily indicated that PABPC1 can interact with FAM134B mRNA and promote its translation. Taken together, this study revealed the role of the PABPC1-FAM134B-ER-phagy pathway on ferroptosis, providing important evidence for novel anti-cancer strategies.