Modulation of protease expression by the transcription factor Ptx1/PITX regulates protein quality control during aging

• Published in: Cell reports (Cambridge) 2023-01, Vol.42 (1), p.111970-111970, Article 111970
• Main Authors: Jiao, Jianqin, Curley, Michelle, Graca, Flavia A., Robles-Murguia, Maricela, Shirinifard, Abbas, Finkelstein, David, Xu, Beisi, Fan, Yiping, Demontis, Fabio
• Format: Article
• Language: English
• Subjects: aging; Aging - metabolism; Animals; betaTry; CP: Cell biology; CP: Molecular biology; Drosophila; Endopeptidases - metabolism; Humans; huntingtin; peptidase; PITX; protease; Proteasome Endopeptidase Complex - metabolism; protein quality control; Proteolysis; proteostasis; Ptx1; skeletal muscle; Transcription Factors - metabolism; Ubiquitins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111970

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. [Display omitted] •Age-dependent downregulation of protease expression impairs muscle proteostasis•The protein levels of the transcription factor Ptx1 increase with aging in muscle•Ptx1 knockdown increases the expression of age-downregulated proteases•Ptx1 RNAi improves muscle proteostasis via proteases and extends lifespan 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.