Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis.

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

Journal: Nature cell biology 2023;25(3):404-414

PMID: 36747082

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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 SLC7A11 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 SLC7A11 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 SLC7A11 cancer cells and suppress SLC7A11 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.

Address: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Kadmon Corporation (A Sanofi Company), LLC, New York, NY, USA.; The Barer Institute, Philadelphia, PA, USA.; Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. [email protected].; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. [email protected].

DOI: 10.1038/s41556-023-01091-2