UBXN7 cofactor of CRL3 KEAP1 and CRL2 VHL ubiquitin ligase complexes mediates reciprocal regulation of NRF2 and HIF-1α proteins

• Published in: Biochimica et biophysica acta. Molecular cell research Vol. 1868; no. 4; p. 118963
• Main Authors: Di Gregorio, Jacopo, Cilenti, Lucia, Ambivero, Camilla T, Andl, Thomas, Liao, Ronglih, Zervos, Antonis S
• Format: Journal Article
• Language: English
• Published: Netherlands 01-04-2021
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Cell Hypoxia; Gene Expression Regulation; Gene Knockdown Techniques; Glycolysis; HEK293 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Kelch-Like ECH-Associated Protein 1 - metabolism; NF-E2-Related Factor 2 - metabolism; Oxidative Phosphorylation; Oxidative Stress; Ubiquitin-Protein Ligases - metabolism; Oxidative stress; NRF2; Glycolysis; MUL1; UBXN7; HIF-1α
• ISSN: 1879-2596

UBXN7 is a cofactor protein that provides a scaffold for both CRL3
and CRL2
ubiquitin ligase complexes involved in the regulation of the NRF2 and HIF-1α protein levels respectively. NRF2 and HIF-1α are surveillance transcription factors that orchestrate the cellular response to oxidative stress (NRF2) or to hypoxia (HIF-1α). Since mitochondria are the main oxygen sensors as well as the principal producers of ROS, it can be presumed that they may be able to modulate the activity of CRL3
and CRL2
complexes in response to stress. We have uncovered a new mechanism of such regulation that involves the UBXN7 cofactor protein and its regulation by mitochondrial MUL1 E3 ubiquitin ligase. High level of UBXN7 leads to HIF-1α accumulation, whereas low level of UBXN7 correlates with an increase in NRF2 protein. The reciprocal regulation of HIF-1α and NRF2 by UBXN7 is coordinated under conditions of oxidative stress or hypoxia. In addition, this molecular mechanism leads to different metabolic states; high level of UBXN7 and accumulation of HIF-1α support glycolysis, whereas inactivation of UBXN7 and activation of NRF2 confer increased OXPHOS. We describe a new mechanism by which MUL1 E3 ubiquitin ligase modulates the UBXN7 cofactor protein level and provides a reciprocal regulation of CRL3
and CRL2
ubiquitin ligase complexes. Furthermore, we delineate how this regulation is reflected in NRF2 and HIF-1α accumulation and determines the metabolic state as well as the adaptive response to mitochondrial stress.