Actin Cytoskeleton Vulnerability to Disulfide Stress Mediates Disulfidptosis

Authors

Xiaoguang Liu
Litong Nie
Yilei Zhang
Yuelong Yan
Chao Wang
Medina Colic
Kellen Olszewski
Amber Horbath
Xiong Chen
Guang Lei
Chao Mao
Shiqi Wu
Li Zhuang
Masha V Poyurovsky
M James You
Traver Hart
Daniel D Billadeau
Junjie Chen
Boyi Gan

Publication Date

3-1-2023

Journal

Nature Cell Biology

Abstract

SLC7A11-mediated cystine uptake suppresses ferroptosis yet promotes cell death under glucose starvation; the nature of the latter cell death remains unknown. Here we show that aberrant accumulation of intracellular disulfides in SLC7A11high cells under glucose starvation induces a previously uncharacterized form of cell death distinct from apoptosis and ferroptosis. We term this cell death disulfidptosis. Chemical proteomics and cell biological analyses showed that glucose starvation in SLC7A11high cells induces aberrant disulfide bonds in actin cytoskeleton proteins and F-actin collapse in a SLC7A11-dependent manner. CRISPR screens and functional studies revealed that inactivation of the WAVE regulatory complex (which promotes actin polymerization and lamellipodia formation) suppresses disulfidptosis, whereas constitutive activation of Rac promotes disulfidptosis. We further show that glucose transporter inhibitors induce disulfidptosis in SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results reveal that the susceptibility of the actin cytoskeleton to disulfide stress mediates disulfidptosis and suggest a therapeutic strategy to target disulfidptosis in cancer treatment.

Keywords

Humans, Disulfides, Neoplasms, Apoptosis, Actin Cytoskeleton, Glucose

Comments

Supplementary Materials

PMID: 36747082