| First Author | Chillappagari S | Year | 2020 |
| Journal | Sci Rep | Volume | 10 |
| Issue | 1 | Pages | 2268 |
| PubMed ID | 32042051 | Mgi Jnum | J:297857 |
| Mgi Id | MGI:6479339 | Doi | 10.1038/s41598-020-59005-3 |
| Citation | Chillappagari S, et al. (2020) SIAH2-mediated and organ-specific restriction of HO-1 expression by a dual mechanism. Sci Rep 10(1):2268 |
| abstractText | 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. |
