The MARCHF6 E3 Ubiquitin Ligase Acts As an NADPH Sensor for the Regulation of Ferroptosis

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2022 Aug 8

PMID 35941365

Authors

Kha The Nguyen

Sang-Hyeon Mun

Jihye Yang

Jongeun Lee

Ok-Hee Seok

Eunjeong Kim

Dasom Kim

So Young An

Dong-Young Seo

Jeong-Yong Suh

Yoontae Lee

Cheol-Sang Hwang

Affiliations

Soon will be listed here.

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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