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

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

PROVIDER: PRJNA657572 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12462650_1.fastq.gz	Fastqsanger.gz
	SRR12462650_2.fastq.gz	Fastqsanger.gz
	SRR12462651_1.fastq.gz	Fastqsanger.gz
	SRR12462651_2.fastq.gz	Fastqsanger.gz
	SRR12462652_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

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

Project description: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.

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