Modulation of protease expression by PITX transcription factors regulates protein quality control during aging

Protein quality control is important for healthy aging and is dysregulated in several age-related diseases. The autophagy-lysosome and ubiquitin-proteasome systems are key for proteostasis but it remains largely unknown whether other proteolytic systems maintain protein quality control during aging. Here, we find that the expression of proteolytic enzymes (proteases/peptidases) distinct from the autophagy-lysosome and ubiquitin-proteasome systems declines during skeletal muscle aging in Drosophila. Age-dependent downregulation of proteases undermines proteostasis, as demonstrated by the increase in detergent-insoluble poly-ubiquitinated proteins and pathogenic huntingtin-polyQ in response to protease RNAi. Transcriptomic analysis identifies Ptx1, homologous to human PITX1/2/3, as a transcriptional regulator of proteases. Specifically, RNAi for Ptx1 increases the expression of age-downregulated proteases and improves protein quality. Moreover, muscle-specific expression of Ptx1 RNAi extends lifespan. These findings indicate that protein quality control is ensured during aging by autophagy/proteasome-independent proteases that degrade misfolded and aggregation-prone proteins and by their transcriptional modulator Ptx1. Here 3 Drosophila melanogaster RNA seq samples treated with Pitx RNAi are compred to control samples from GSE149799: GSM4512833 FD_GFP_1TH GSM4512834 FD_GFP_2TH GSM4512835 FD_GFP_3TH GSM4512836 FD_white_1TH GSM4512837 FD_white_2TH GSM4512838 FD_white_3TH