Proteasome gene expression is controlled by coordinated functions of multiple transcription factors.

IF 7.4 1区 生物学 Q1 CELL BIOLOGY Journal of Cell Biology Pub Date : 2024-08-05 Epub Date: 2024-05-20 DOI:10.1083/jcb.202402046
Jennifer E Gilda, Asrafun Nahar, Dharanibalan Kasiviswanathan, Nadav Tropp, Tamar Gilinski, Tamar Lahav, Dina Alexandrovich, Yael Mandel-Gutfreund, Soyeon Park, Shenhav Shemer
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Abstract

Proteasome activity is crucial for cellular integrity, but how tissues adjust proteasome content in response to catabolic stimuli is uncertain. Here, we demonstrate that transcriptional coordination by multiple transcription factors is required to increase proteasome content and activate proteolysis in catabolic states. Using denervated mouse muscle as a model system for accelerated proteolysis in vivo, we reveal that a two-phase transcriptional program activates genes encoding proteasome subunits and assembly chaperones to boost an increase in proteasome content. Initially, gene induction is necessary to maintain basal proteasome levels, and in a more delayed phase (7-10 days after denervation), it stimulates proteasome assembly to meet cellular demand for excessive proteolysis. Intriguingly, the transcription factors PAX4 and α-PALNRF-1 control the expression of proteasome among other genes in a combinatorial manner, driving cellular adaptation to muscle denervation. Consequently, PAX4 and α-PALNRF-1 represent new therapeutic targets to inhibit proteolysis in catabolic diseases (e.g., type-2 diabetes, cancer).

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蛋白酶体基因的表达受多种转录因子协调功能的控制。
蛋白酶体的活性对细胞的完整性至关重要,但目前还不清楚组织如何调整蛋白酶体的含量以应对分解代谢的刺激。在这里,我们证明了在分解代谢状态下增加蛋白酶体含量和激活蛋白水解需要多个转录因子的转录协调。我们利用失去神经支配的小鼠肌肉作为体内加速蛋白分解的模型系统,揭示了一个两阶段转录程序激活编码蛋白酶体亚基和组装伴侣的基因,以促进蛋白酶体含量的增加。起初,基因诱导是维持蛋白酶体基础水平所必需的,而在更延迟的阶段(去神经支配后 7-10 天),基因诱导刺激蛋白酶体组装,以满足细胞对过度蛋白分解的需求。耐人寻味的是,转录因子 PAX4 和 α-PALNRF-1 以组合方式控制蛋白酶体和其他基因的表达,推动细胞适应肌肉去神经化。因此,PAX4 和 α-PALNRF-1 是抑制分解代谢疾病(如 2 型糖尿病、癌症)中蛋白酶解的新治疗靶点。
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来源期刊
Journal of Cell Biology
Journal of Cell Biology 生物-细胞生物学
CiteScore
12.60
自引率
2.60%
发文量
213
审稿时长
1 months
期刊介绍: The Journal of Cell Biology (JCB) is a comprehensive journal dedicated to publishing original discoveries across all realms of cell biology. We invite papers presenting novel cellular or molecular advancements in various domains of basic cell biology, along with applied cell biology research in diverse systems such as immunology, neurobiology, metabolism, virology, developmental biology, and plant biology. We enthusiastically welcome submissions showcasing significant findings of interest to cell biologists, irrespective of the experimental approach.
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