Overexpression of Nfe2l1 increases proteasome activity and delays vision loss in a preclinical model of human blindness.
Overexpression of Nfe2l1 increases proteasome activity and delays vision loss in a preclinical model of human blindness.
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DOI：
10.1126/sciadv.add5479
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发表时间：
2023-07-14
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
蛋白酶体是蛋白质分解的中心机器，对分解人类细胞中大多数受损和异常的蛋白质是至关重要的。虽然还没有普遍适用的药物，但对蛋白酶体活性的刺激正在被分析为增加细胞对广泛的蛋白毒性应激源的抵抗力的原则验证策略。这些方法包括通过个别蛋白酶体亚基的过度表达、磷酸化或由小分子或多肽诱导的构象变化来刺激蛋白酶体。与这些方法相反，我们评估了转录驱动的总蛋白酶体库的增加，以增强退化的视网膜神经元的蛋白分解能力。我们发现，核因子红系2样蛋白1(NFe2l1)转录因子的过表达刺激了蛋白酶体的生物生成和活性，改善了泛素-蛋白酶体报告基因的清除，并延缓了由错误折叠的蛋白导致的临床前小鼠模型中光感受器神经元的丢失。这一发现突显了NFe2l1作为治疗与蛋白质错误折叠有关的神经退行性疾病的新兴治疗靶点。增加蛋白酶体的数量可能有助于减轻与蛋白平衡失调相关的人类疾病。
Proteasomes are the central proteolytic machines that are critical for breaking down most of the damaged and abnormal proteins in human cells. Although universally applicable drugs are not yet available, the stimulation of proteasomal activity is being analyzed as a proof-of-principle strategy to increase cellular resistance to a broad range of proteotoxic stressors. These approaches have included the stimulation of proteasomes through the overexpression of individual proteasome subunits, phosphorylation, or conformational changes induced by small molecules or peptides. In contrast to these approaches, we evaluated a transcription-driven increase in the total proteasome pool to enhance the proteolytic capacity of degenerating retinal neurons. We show that overexpression of nuclear factor erythroid-2-like 1 (Nfe2l1) transcription factor stimulated proteasome biogenesis and activity, improved the clearance of the ubiquitin-proteasomal reporter, and delayed photoreceptor neuron loss in a preclinical mouse model of human blindness caused by misfolded proteins. The findings highlight Nfe2l1 as an emerging therapeutic target to treat neurodegenerative diseases linked to protein misfolding. Increasing amounts of proteasomes might help to mitigate human diseases linked to proteostasis dysregulation.
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影响因子：
16.6
作者：
Choi WH;de Poot SA;Lee JH;Kim JH;Han DH;Kim YK;Finley D;Lee MJ
通讯作者：
Lee MJ
垃圾谈话：转录级别的哺乳动物蛋白酶体调节。
DOI：
10.1016/j.tig.2020.09.005
发表时间：
2021-03
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
Kamber Kaya HE;Radhakrishnan SK
通讯作者：
Radhakrishnan SK
DOI：
10.1083/jcb.201709072
发表时间：
2018-01-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Klaips CL;Jayaraj GG;Hartl FU
通讯作者：
Hartl FU
影响因子：
5.5
作者：
Cheng SY;Malachi A;Cipi J;Ma S;Brush RS;Agbaga MP;Punzo C
通讯作者：
Punzo C
影响因子：
0.8
作者：
Benchorin, Gillie;Calton, Melissa A.;Vollrath, Douglas
通讯作者：
Vollrath, Douglas