Regulation of energy homeostasis by the ubiquitin-independent REGγ proteasome

Nat Commun. 2016 Aug 11;7:12497. doi: 10.1038/ncomms12497.

Abstract

Maintenance of energy homeostasis is essential for cell survival. Here, we report that the ATP- and ubiquitin-independent REGγ-proteasome system plays a role in maintaining energy homeostasis and cell survival during energy starvation via repressing rDNA transcription, a major intracellular energy-consuming process. Mechanistically, REGγ-proteasome limits cellular rDNA transcription and energy consumption by targeting the rDNA transcription activator SirT7 for ubiquitin-independent degradation under normal conditions. Moreover, energy starvation induces an AMPK-directed SirT7 phosphorylation and subsequent REGγ-dependent SirT7 subcellular redistribution and degradation, thereby further reducing rDNA transcription to save energy to overcome cell death. Energy starvation is a promising strategy for cancer therapy. Our report also shows that REGγ knockdown markedly improves the anti-tumour activity of energy metabolism inhibitors in mice. Our results underscore a control mechanism for an ubiquitin-independent process in maintaining energy homeostasis and cell viability under starvation conditions, suggesting that REGγ-proteasome inhibition has a potential to provide tumour-starving benefits.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / metabolism*
  • Cell Survival
  • Cytoplasm / metabolism
  • DNA, Ribosomal / metabolism
  • HCT116 Cells
  • HEK293 Cells
  • HeLa Cells
  • Homeostasis*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Nude
  • Neoplasms / therapy*
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism*
  • Ubiquitin / metabolism

Substances

  • Autoantigens
  • DNA, Ribosomal
  • Ki antigen
  • Ubiquitin
  • Proteasome Endopeptidase Complex