The intracellular levels of the cytoprotective enzyme heme oxygenase-1 (HO-1) are tightly controlled. Here, we reveal a novel mechanism preventing the exaggerated expression of HO-1. The analysis of mice with a knock-out in the ubiquitin E3 ligase seven in absentia homolog 2 (SIAH2) showed elevated HO-1 protein levels in specific organs such as heart, kidney and skeletal muscle. Increased HO-1 protein amounts were also seen in human cells deleted for the SIAH2 gene. The higher HO-1 levels are not only due to an increased protein stability but also to elevated expression of the HO-1 encoding HMOX1 gene, which depends on the transcription factor nuclear factor E2-related factor 2 (NRF2), a known SIAH2 target. Dependent on its RING (really interesting new gene) domain, expression of SIAH2 mediates proteasome-dependent degradation of its interaction partner HO-1. Additionally SIAH2-deficient cells are also characterized by reduced expression levels of glutathione peroxidase 4 (GPX4), rendering the knock-out cells more sensitive to ferroptosis.
- Chillappagari, S.
- Belapurkar, R.
- Möller, A.
- Molenda, N.
- Kracht, M.
- Rohrbach, S.
- Schmitz, M. L.
Keywords
- Animals
- CRISPR-Cas Systems/genetics
- Down-Regulation
- Ferroptosis
- Fibroblasts
- Gene Knockdown Techniques
- HEK293 Cells
- Heme Oxygenase-1/genetics/*metabolism
- Humans
- Membrane Proteins/genetics/*metabolism
- Mice
- Mice, Knockout
- NF-E2-Related Factor 2/*metabolism
- Nuclear Proteins/genetics/*metabolism
- Oxygen/metabolism
- Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism
- Primary Cell Culture
- Proteasome Endopeptidase Complex/metabolism
- Protein Domains
- Protein Stability
- Proteolysis
- Ubiquitin-Protein Ligases/genetics/*metabolism
- Ubiquitination
