한빛사 논문
Kha The Nguyen 1, Sang-Hyeon Mun 1, Jihye Yang 1, Jongeun Lee 1, Ok-Hee Seok1, Eunjeong Kim 1, Dasom Kim 1, So Young An2, Dong-Young Seo1, Jeong-Yong Suh2, Yoontae Lee 1,* and Cheol-Sang Hwang 1,*
1Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea. 2Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea.
*Corresponding author.
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.
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