The CRTC-CREB axis functions as a transcriptional sensor to protect against proteotoxic stress in Drosophila.
The CRTC-CREB axis functions as a transcriptional sensor to protect against proteotoxic stress in Drosophila.
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CRTC-CREB 轴作为转录传感器发挥作用，以防止果蝇免受蛋白毒性应激
DOI：
10.1038/s41419-022-05122-y
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发表时间：
2022-08-06
影响因子：
9
通讯作者：
Deng, Hansong
中科院分区：
文献类型：
--
作者：
Yin, Youjie;Ma, Peng;Wang, Saifei;Zhang, Yao;Han, Ruolei;Huo, Chunyu;Wu, Meixian;Deng, Hansong
cAMP负责元件结合蛋白（CREB）是一种进化保守的转录因子，调控细胞生长、突触可塑性等。在这项研究中，我们意外地发现蛋白酶体抑制剂，如MLN2238，通过大规模的化合物筛选，在成年苍蝇中稳健地增加CREB活性。从机制上讲，蛋白酶体抑制产生的活性氧（ROS）是必需的，并且足以通过c-Jun n -末端激酶（JNK）促进CREB活性。在293 T细胞中，MLN2238激活JNK也是CREB Ser133磷酸化增加所必需的。同时，对果蝇肠道的转录组分析发现，一组参与氧化还原和蛋白质抑制调节的基因通过过表达CRTC （creb调节的转录辅激活因子）而增强。有趣的是，在果蝇亨廷顿舞蹈病（HD）模型中，肌肉中CRTC的过表达强有力地恢复了蛋白质折叠和蛋白酶体活性，并改善了HD相关的发病机制，如蛋白质聚集、运动性和寿命。此外，CREB活性随着年龄的增长而增加，进一步增强其活性可以抑制衰老肌肉中的蛋白质聚集。总之，我们的研究结果确定了CRTC/CREB下游ROS/JNK信号作为一个保守的传感器来处理氧化和蛋白质毒性应激。提高CRTC/CREB活性是治疗衰老相关蛋白聚集性疾病的潜在治疗策略。
cAMP Responsible Element Binding Protein (CREB) is an evolutionarily conserved transcriptional factor that regulates cell growth, synaptic plasticity and so on. In this study, we unexpectedly found proteasome inhibitors, such as MLN2238, robustly increase CREB activity in adult flies through a large-scale compound screening. Mechanistically, reactive oxidative species (ROS) generated by proteasome inhibition are required and sufficient to promote CREB activity through c-Jun N-terminal kinase (JNK). In 293 T cells, JNK activation by MLN2238 is also required for increase of CREB phosphorylation at Ser133. Meanwhile, transcriptome analysis in fly intestine identified a group of genes involved in redox and proteostatic regulation are augmented by overexpressing CRTC (CREB-regulated transcriptional coactivator). Intriguingly, CRTC overexpression in muscles robustly restores protein folding and proteasomal activity in a fly Huntington’s disease (HD) model, and ameliorates HD related pathogenesis, such as protein aggregates, motility, and lifespan. Moreover, CREB activity increases during aging, and further enhances its activity can suppress protein aggregates in aged muscles. Together, our results identified CRTC/CREB downstream ROS/JNK signaling as a conserved sensor to tackle oxidative and proteotoxic stresses. Boosting CRTC/CREB activity is a potential therapeutic strategy to treat aging related protein aggregation diseases.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
DOI：
10.1073/pnas.0702726104
发表时间：
2007-05-15
影响因子：
11.1
作者：
Ja, William W.;Carvalho, Gil B.;Benzer, Seymour
通讯作者：
Benzer, Seymour
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
9.8
作者：
David DC;Ollikainen N;Trinidad JC;Cary MP;Burlingame AL;Kenyon C
通讯作者：
Kenyon C
影响因子：
3.5
作者：
Arthur, JSC;Cohen, P
通讯作者：
Cohen, P