Regulation of energy homeostasis by the ubiquitin-independent REG? proteasome.

ABSTRACT: Maintenance of energy homeostasis is essential for cell survival. Here, we report that the ATP- and ubiquitin-independent REG?-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, REG?-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 REG?-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 REG? 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 REG?-proteasome inhibition has a potential to provide tumour-starving benefits.

SUBMITTER: Sun L 

PROVIDER: S-EPMC4987533 | biostudies-other | 2016

REPOSITORIES: biostudies-other