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用蛋白酶体抑制剂进行脉冲处理的细胞中蛋白酶体活性的早期恢复与DDI2无关。

Early recovery of proteasome activity in cells pulse-treated with proteasome inhibitors is independent of DDI2.

作者信息

Ibtisam Ibtisam, Kisselev Alexei F

机构信息

Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, 720 S. Donahue Dr. Auburn AL 36849 USA.

出版信息

bioRxiv. 2023 Nov 28:2023.08.03.550647. doi: 10.1101/2023.08.03.550647.

DOI:10.1101/2023.08.03.550647
PMID:37577495
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10418215/
Abstract

Rapid recovery of proteasome activity may contribute to intrinsic and acquired resistance to FDA-approved proteasome inhibitors. Previous studies have demonstrated that the expression of proteasome genes in cells treated with sub-lethal concentrations of proteasome inhibitors is upregulated by the transcription factor Nrf1 (NFE2L1), which is activated by a DDI2 protease. Here, we demonstrate that the recovery of proteasome activity is DDI2-independent and occurs before transcription of proteasomal genes is upregulated but requires protein translation. Thus, mammalian cells possess an additional DDI2 and transcription-independent pathway for the rapid recovery of proteasome activity after proteasome inhibition.

摘要

蛋白酶体活性的快速恢复可能导致对FDA批准的蛋白酶体抑制剂产生内在和获得性抗性。先前的研究表明，用亚致死浓度的蛋白酶体抑制剂处理的细胞中，蛋白酶体基因的表达由转录因子Nrf1（NFE2L1）上调，而Nrf1由DDI2蛋白酶激活。在此，我们证明蛋白酶体活性的恢复不依赖于DDI2，且发生在蛋白酶体基因转录上调之前，但需要蛋白质翻译。因此，哺乳动物细胞在蛋白酶体抑制后具有另一种不依赖于DDI2和转录的途径来实现蛋白酶体活性的快速恢复。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/194b/10695208/ca504282ca85/nihpp-2023.08.03.550647v2-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/194b/10695208/a3fabacece8a/nihpp-2023.08.03.550647v2-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/194b/10695208/561c59e0a8af/nihpp-2023.08.03.550647v2-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/194b/10695208/1a56a9b70929/nihpp-2023.08.03.550647v2-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/194b/10695208/ca504282ca85/nihpp-2023.08.03.550647v2-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/194b/10695208/a3fabacece8a/nihpp-2023.08.03.550647v2-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/194b/10695208/561c59e0a8af/nihpp-2023.08.03.550647v2-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/194b/10695208/1a56a9b70929/nihpp-2023.08.03.550647v2-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/194b/10695208/ca504282ca85/nihpp-2023.08.03.550647v2-f0004.jpg

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本文引用的文献

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Sci Adv. 2023 Jul 14;9(28):eadd5479. doi: 10.1126/sciadv.add5479.
2
NEIL3-mediated proteasomal degradation facilitates the repair of cisplatin-induced DNA damage in human cells.NEIL3 介导的蛋白酶体降解有助于修复人细胞中的顺铂诱导的 DNA 损伤。
Sci Rep. 2023 Mar 30;13(1):5174. doi: 10.1038/s41598-023-32186-3.
3
DDI2 promotes tumor metastasis and resists antineoplastic drugs-induced apoptosis in colorectal cancer.
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Apoptosis. 2023 Apr;28(3-4):458-470. doi: 10.1007/s10495-022-01796-z. Epub 2022 Dec 15.
4
The protease DDI2 regulates NRF1 activation in response to cadmium toxicity.蛋白酶DDI2在应对镉毒性时调节NRF1的激活。
iScience. 2022 Sep 27;25(10):105227. doi: 10.1016/j.isci.2022.105227. eCollection 2022 Oct 21.
5
The aspartyl protease DDI2 drives adaptation to proteasome inhibition in multiple myeloma.天冬氨酸蛋白酶 DDI2 驱动多发性骨髓瘤对蛋白酶体抑制的适应性。
Cell Death Dis. 2022 May 19;13(5):475. doi: 10.1038/s41419-022-04925-3.
6
Mammalian Ddi2 is a shuttling factor containing a retroviral protease domain that influences binding of ubiquitylated proteins and proteasomal degradation.哺乳动物的Ddi2是一种穿梭因子，含有一个逆转录病毒蛋白酶结构域，该结构域影响泛素化蛋白的结合和蛋白酶体降解。
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