Hydrogen-driven remodeling of molecular networks by the nucleolar architecture

Abstract

Acidosis protects cells facing low oxygen tension (hypoxia) in various physiological and pathological settings that include muscle exercise, tumor development, and ischemic disorders. A central element in the adaptive response to low oxygen tension is HIF (hypoxia-inducible factor), a transcription factor that activates an array of genes implicated in oxygen homeostasis, tumour vascularization and ischemic preconditioning. HIF is activated by hypoxia, but undergoes degradation by the VHL (von Hippel-Lindau) tumour suppressor ubiquitin ligase complex in the presence of oxygen. Here, we uncover a gene-regulatory and energy homeostasis process that relies on the cooperation between acidosis, VHL, and the nucleolus. Cellular sensing of increased environmental hydrogen ion (H+) concentration, triggered by Pasteur or Warburg hyperglycolytic effects, allows the nucleolar architecture, or more specifically the intergenic spacers (IGS) of rRNA genes (rDNA), to capture and confine VHL to nucleoli by converting the protein from a dynamic to a static state. This phenomenon is reverted following the re-instatement of neutral pH conditions. A protein surface region of VHL was identified as a discrete H+-responsive nucleolar detention signal. More importantly, nucleolar sequestration of VHL enables HIF to evade destruction in the presence of oxygen and activate its target genes. Strikingly, H+-dependent trapping of VHL to IGS restricts rDNA transcription limiting ribosomal biogenesis, the most energy-demanding cellular process. rDNA silencing harmonizes ATP demand with limited anaerobic supply to preserve energy equilibrium and viability under hypoxia. These findings reveal that H+ controls gene expression and cellular energy demand, and provide an explanation for the protective effect of acidosis in ischemic settings such as development, stroke, and cancer.