| Literature DB >> 35941365 |
Kha The Nguyen1, Sang-Hyeon Mun1, Jihye Yang1, Jongeun Lee1, Ok-Hee Seok1, Eunjeong Kim1, Dasom Kim1, So Young An2, Dong-Young Seo1, Jeong-Yong Suh2, Yoontae Lee3, Cheol-Sang Hwang4.
Abstract
Ferroptosis is a unique form of cell death caused by excessive iron-dependent lipid peroxidation. The level of the anabolic reductant NADPH is a biomarker of ferroptosis sensitivity. However, specific regulators that detect cellular NADPH levels, thereby modulating downstream ferroptosis cascades, are largely unknown. We show here that the transmembrane endoplasmic reticulum MARCHF6 E3 ubiquitin ligase recognizes NADPH through its C-terminal regulatory region. This interaction upregulates the E3 ligase activity of MARCHF6, thus downregulating ferroptosis. We also found that MARCHF6 mediates the degradation of the key ferroptosis effectors ACSL4 and p53. Furthermore, inhibiting ferroptosis rescued the growth of MARCHF6-deficient tumours and peri-natal lethality of Marchf6-/- mice. Together, these findings identify MARCHF6 as a previously unknown NADPH sensor in the ubiquitin system and a crucial regulator of ferroptosis.Entities:
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Year: 2022 PMID： 35941365 DOI： 10.1038/s41556-022-00973-1
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.213