Modulation of protease expression by the transcription factor Ptx1/PITX regulates protein quality control during aging.
Modulation of protease expression by the transcription factor Ptx1/PITX regulates protein quality control during aging.
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DOI：
10.1016/j.celrep.2022.111970
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发表时间：
2023-01-31
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
蛋白质质量控制对于健康老龄化很重要，并且在与年龄相关的疾病中失调。自噬-溶酶体和泛素-蛋白酶体是蛋白质稳态的关键，但在很大程度上还不清楚其他蛋白水解系统是否也有助于维持衰老过程中的蛋白质稳态。在这里，我们发现，蛋白水解酶（蛋白酶/肽酶）的表达不同的自噬溶酶体和泛素蛋白酶体系统下降，在果蝇骨骼肌老化。蛋白酶依赖性蛋白酶下调破坏蛋白质稳态，如通过响应于蛋白酶敲低的洗涤剂不溶性聚泛素化蛋白和致病性亨廷顿蛋白-polyQ水平的增加所证明的。计算分析确定的转录因子Ptx 1（同源的人PITX 1/2/3）作为蛋白酶表达的调节。与该模型一致，Ptx 1蛋白水平随着衰老而增加，Ptx 1 RNAi抵消了与年龄相关的蛋白酶表达下调。此外，Ptx 1 RNAi以蛋白酶依赖性方式改善肌肉蛋白质质量控制并延长寿命。这些发现表明，蛋白酶及其转录调节因子Ptx 1确保了衰老过程中的蛋白稳态。Jiao等人发现果蝇骨骼肌衰老过程中蛋白酶表达下降，这破坏了蛋白质稳态。他们鉴定了转录因子Ptx 1/PITX作为蛋白酶表达的阻遏物，并表明Ptx 1/PITX敲低以蛋白酶依赖的方式改善了衰老过程中的肌肉蛋白质质量控制，并延长了寿命。
Protein quality control is important for healthy aging and is dysregulated in age-related diseases. The autophagy-lysosome and ubiquitin-proteasome are key for proteostasis, but it remains largely unknown whether other proteolytic systems also contribute to maintain proteostasis during aging. Here, we find that expression of proteolytic enzymes (proteases/peptidases) distinct from the autophagy-lysosome and ubiquitin-proteasome systems declines during skeletal muscle aging in Drosophila. Age-dependent protease downregulation undermines proteostasis, as demonstrated by the increase in detergent-insoluble poly-ubiquitinated proteins and pathogenic huntingtin-polyQ levels in response to protease knockdown. Computational analyses identify the transcription factor Ptx1 (homologous to human PITX1/2/3) as a regulator of protease expression. Consistent with this model, Ptx1 protein levels increase with aging, and Ptx1 RNAi counteracts the age-associated downregulation of protease expression. Moreover, Ptx1 RNAi improves muscle protein quality control in a protease-dependent manner and extends lifespan. These findings indicate that proteases and their transcriptional modulator Ptx1 ensure proteostasis during aging. Jiao et al. find that protease expression declines during skeletal muscle aging in Drosophila and that this undermines proteostasis. They identify the transcription factor Ptx1/PITX as a repressor of protease expression and show that Ptx1/PITX knockdown improves muscle protein quality control during aging in a protease-dependent manner and extends lifespan.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
4.5
作者：
Bai H;Kang P;Hernandez AM;Tatar M
通讯作者：
Tatar M
影响因子：
5.8
作者：
Arganda-Carreras, Ignacio;Kaynig, Verena;Seung, H. Sebastian
通讯作者：
Seung, H. Sebastian
影响因子：
8.8
作者：
Dutta, Devanjali;Dobson, Adam J.;Buchon, Nicolas
通讯作者：
Buchon, Nicolas
影响因子：
--
作者：
Charles, MA;Suh, H;Gage, PJ
通讯作者：
Gage, PJ