Spautin-1 inhibits mitochondrial complex I and leads to suppression of the unfolded protein response and cell survival during glucose starvation.
Spautin-1 inhibits mitochondrial complex I and leads to suppression of the unfolded protein response and cell survival during glucose starvation.
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DOI：
10.1038/s41598-022-15673-x
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发表时间：
2022-07-07
影响因子：
4.6
通讯作者：
Tomida, Akihiro
中科院分区：
文献类型：
--
作者：
Kunimasa, Kazuhiro;Ikeda-Ishikawa, Chika;Tani, Yuri;Tsukahara, Satomi;Sakurai, Junko;Okamoto, Yuka;Koido, Masaru;Dan, Shingo;Tomida, Akihiro
未折叠蛋白反应（UPR）是一种适应性应激反应途径，对于内质网应激（例如葡萄糖饥饿期间）下的癌细胞生存至关重要。在这项研究中，我们确定了spautin-1，一种抑制泛素特异性肽酶10（USP 10）和USP 13的自噬抑制剂，作为葡萄糖饥饿条件下的一种新型UPR抑制剂。Spaetin-1阻止诱导UPR相关蛋白，包括葡萄糖调节蛋白78，激活转录因子4和x-box结合蛋白-1的剪接变体，并在葡萄糖饥饿的癌细胞中显示出优先的细胞毒性。然而，在葡萄糖饥饿期间，USP 10和USP 13沉默和用其他自噬抑制剂处理未能导致UPR抑制和优先细胞毒性。使用基于转录组和化学敏感性的比较分析，我们确定了spautin-1和线粒体复合物I抑制剂之间的相似性，并发现spautin-1抑制从分离的线粒体中提取的复合物I的活性。我们的研究结果表明，spautin-1可能是一个有吸引力的靶向种子化合物，抑制UPR和癌细胞生存期间葡萄糖饥饿。
The unfolded protein response (UPR) is an adaptive stress response pathway that is essential for cancer cell survival under endoplasmic reticulum stress such as during glucose starvation. In this study, we identified spautin-1, an autophagy inhibitor that suppresses ubiquitin-specific peptidase 10 (USP10) and USP13, as a novel UPR inhibitor under glucose starvation conditions. Spautin-1 prevented the induction of UPR-associated proteins, including glucose-regulated protein 78, activating transcription factor 4, and a splicing variant of x-box-binding protein-1, and showed preferential cytotoxicity in glucose-starved cancer cells. However, USP10 and USP13 silencing and treatment with other autophagy inhibitors failed to result in UPR inhibition and preferential cytotoxicity during glucose starvation. Using transcriptome and chemosensitivity-based COMPARE analyses, we identified a similarity between spautin-1 and mitochondrial complex I inhibitors and found that spautin-1 suppressed the activity of complex I extracted from isolated mitochondria. Our results indicated that spautin-1 may represent an attractive mitochondria-targeted seed compound that inhibits the UPR and cancer cell survival during glucose starvation.
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