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<p>The proteasome is essential for cellular protein homeostasis through selective destruction of damaged and misfolded proteins. Failure of proteasome-dependent turnover accompanied by accumulation and aggregation of aberrant proteins is a hallmark of aging and late-onset neurodegenerative diseases. SKN-1A/Nrf1, a member of the NFE2L/Nrf family of transcription factors, is a master regulator of proteasome biogenesis. Through transcriptional control of proteasome subunit gene expression, SKN-1A/Nrf1 controls homoeostatic and stress-responsive upregulation of proteasome levels in adaptation to proteasome dysfunction or protein misfolding. SKN-1A/Nrf1 acts in concert with another Nrf family transcription factor, SKN-1C/Nrf2, to regulate many aspects of physiology including stress responses, redox balance, immunity, and metabolism. Here, we demonstrate that a small deletion in the promoter of the <i>pbs-5</i> gene, which encodes an essential proteasome subunit, uncouples its expression from transcriptional regulation by SKN-1A/Nrf1. This disruption leads to compensatory SKN-1A/Nrf1-dependent upregulation of other proteasome subunit genes, resulting in a homeostatic imbalance in proteasomal gene expression. This <i>pbs-5</i> regulatory mutation phenocopies some, but not all, aspects of SKN-1A/Nrf1 inactivation, providing evidence that coordinated regulation of proteasomal subunit gene expression underlies a subset of SKN-1A/Nrf1’s physiological roles. In comparing the effects of the <i>pbs-5</i> promoter deletion with isoform-specific inactivation of SKN-1A or SKN-1C, we show that the <i>pbs-5</i> promoter mutation completely abrogates multiple lifespan extension paradigms. These results reveal that coordinated homeostatic regulation of proteasome subunit gene expression is critical for longevity and healthy aging.</p>

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Coordinated control of proteasome subunit gene expression promotes stress resistance, proteostasis, and longevity

  • 期刊论文

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  • 发表日期：

    2026年2月17日

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  • Irini Topalidou,
  • Nicolas Lehrbach

摘要

The proteasome is essential for cellular protein homeostasis through selective destruction of damaged and misfolded proteins. Failure of proteasome-dependent turnover accompanied by accumulation and aggregation of aberrant proteins is a hallmark of aging and late-onset neurodegenerative diseases. SKN-1A/Nrf1, a member of the NFE2L/Nrf family of transcription factors, is a master regulator of proteasome biogenesis. Through transcriptional control of proteasome subunit gene expression, SKN-1A/Nrf1 controls homoeostatic and stress-responsive upregulation of proteasome levels in adaptation to proteasome dysfunction or protein misfolding. SKN-1A/Nrf1 acts in concert with another Nrf family transcription factor, SKN-1C/Nrf2, to regulate many aspects of physiology including stress responses, redox balance, immunity, and metabolism. Here, we demonstrate that a small deletion in the promoter of the pbs-5 gene, which encodes an essential proteasome subunit, uncouples its expression from transcriptional regulation by SKN-1A/Nrf1. This disruption leads to compensatory SKN-1A/Nrf1-dependent upregulation of other proteasome subunit genes, resulting in a homeostatic imbalance in proteasomal gene expression. This pbs-5 regulatory mutation phenocopies some, but not all, aspects of SKN-1A/Nrf1 inactivation, providing evidence that coordinated regulation of proteasomal subunit gene expression underlies a subset of SKN-1A/Nrf1’s physiological roles. In comparing the effects of the pbs-5 promoter deletion with isoform-specific inactivation of SKN-1A or SKN-1C, we show that the pbs-5 promoter mutation completely abrogates multiple lifespan extension paradigms. These results reveal that coordinated homeostatic regulation of proteasome subunit gene expression is critical for longevity and healthy aging.