USP13 facilitates a ferroptosis-to-autophagy switch by activation of the NFE2L2/NRF2-SQSTM1/p62-KEAP1 axis dependent on the KRAS signaling pathway.

Ling Chen, Jieling Ning, Li Linghu, Jun Tang, Na Liu, Yao Long, Jingyue Sun, Cairui Lv, Ying Shi, Tania Tao, Desheng Xiao, Ya Cao, Xiang Wang, Shuang Liu, Guangjian Li, Bin Zhang, Yongguang Tao
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Abstract

Macroautophagy/autophagyis a lysosomal-regulated degradation process that participates incellular stress and then promotes cell survival or triggers celldeath. Ferroptosis was initially described as anautophagy-independent, iron-regulated, nonapoptotic cell death.However, recent studies have revealed that autophagy is positivelyassociated with sensitivity to ferroptosis. Nonetheless, themolecular mechanisms by which these two types of regulated cell death(RCD) modulate each other remain largely unclear. Here, we screened85 deubiquitinating enzymes (DUBs) and found that overexpression ofUSP13 (ubiquitin specific peptidase 13) could significantlyupregulate NFE2L2/NRF2 (NFE2 like bZIP transcription factor 2)protein levels. In addition, in 39 cases of KRAS-mutated lungadenocarcinoma (LUAD), we found that approximately 76% of USP13overexpression is positively correlated with NFE2L2 overexpression.USP13 interacts with and catalyzes the deubiquitination of thetranscription factor NFE2L2. Additionally, USP13 depletion promotesan autophagy-to-ferroptosis switch invitro andin xenograft tumor mouse models, through the activation of theNFE2L2-SQSTM1/p62 (sequestosome 1)-KEAP1 axis in KRAS mutant cellsand tumor tissues. Hence, targeting USP13 effectively switchedautophagy-to-ferroptosis, thereby inhibiting KRAS (KRASproto-oncogene, GTPase) mutant LUAD, suggesting the therapeuticpromise of combining autophagy and ferroptosis in the KRAS-mutantLUAD.

USP13 通过激活依赖于 KRAS 信号通路的 NFE2L2/NRF2-SQSTM1/p62-KEAP1 轴,促进铁变态反应向自噬的转换。
大自噬/自噬是一种溶酶体调控的降解过程,它参与细胞应激,然后促进细胞存活或引发细胞死亡。然而,最近的研究发现,自噬与对铁变态反应的敏感性呈正相关。然而,这两种调控细胞死亡(RCD)相互调节的分子机制在很大程度上仍不清楚。在此,我们筛选了85种去泛素化酶(DUBs),发现过表达USP13(泛素特异性肽酶13)可显著调节NFE2L2/NRF2(NFE2 like bZIP transcription factor 2)蛋白水平。此外,在 39 例 KRAS 突变的肺腺癌(LUAD)中,我们发现约 76% 的 USP13 表达与 NFE2L2 的过表达呈正相关。此外,通过激活 KRAS 突变细胞和肿瘤组织中的 NFE2L2-SQSTM1/p62(sequestosome 1)-KEAP1 轴,USP13 的耗竭可在体外和异种移植肿瘤小鼠模型中促进自噬到铁蛋白沉积的转换。因此,靶向 USP13 能有效地将自噬转为铁变态反应,从而抑制 KRAS(KRAS 原癌基因,GTPase)突变型 LUAD,这表明在 KRAS 突变型 LUAD 中结合自噬和铁变态反应具有治疗前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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