SIAH2-mediated and organ-specific restriction of HO-1 expression by a dual mechanism

• Published in: Scientific reports 2020-02, Vol.10 (1), p.2268-2268, Article 2268
• Main Authors: Chillappagari, Shashipavan, Belapurkar, Ratnal, Möller, Andreas, Molenda, Nicole, Kracht, Michael, Rohrbach, Susanne, Schmitz, M. Lienhard
• Format: Article
• Language: English
• Subjects: 631/45/2783; 631/45/474; 631/45/603; Animals; CRISPR-Cas Systems - genetics; Down-Regulation; Ferroptosis; Fibroblasts; Gene Knockdown Techniques; Glutathione peroxidase; HEK293 Cells; Heme; Heme oxygenase (decyclizing); Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Humanities and Social Sciences; Humans; Intracellular levels; Kidneys; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; multidisciplinary; NF-E2-Related Factor 2 - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oxygen - metabolism; Oxygenase; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Primary Cell Culture; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein Domains; Protein Stability; Proteins; Proteolysis; Science; Science (multidisciplinary); Skeletal muscle; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-59005-3

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.