Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis

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 uncharacter...

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Published inNature cell biology Vol. 25; no. 3; pp. 404 - 414
Main Authors Liu, Xiaoguang, Nie, Litong, Zhang, Yilei, Yan, Yuelong, Wang, Chao, Colic, Medina, Olszewski, Kellen, Horbath, Amber, Chen, Xiong, Lei, Guang, Mao, Chao, Wu, Shiqi, Zhuang, Li, Poyurovsky, Masha V, James You, M, Hart, Traver, Billadeau, Daniel D, Chen, Junjie, Gan, Boyi
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 01.03.2023
Subjects
Accumulation
Actin
Actin Cytoskeleton - metabolism
Apoptosis
Biological analysis
Cancer
Cell death
CRISPR
Cystine
Cytoskeleton
Disulfide bonds
Disulfides
Ferroptosis
Glucose
Glucose - metabolism
Glucose transporter
Humans
Inactivation
Lamellipodia
Mortality
Neoplasms - metabolism
Proteins
Proteomics
Pseudopodia
Tumors
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Summary: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.
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B.G. and X.L. conceived and designed the study and wrote most of the manuscript with assistance from L.N.; X.L. performed most of the experiments with assistance from Y.Z., C.W., Y.Y., A.H, X. C., G.L., C.M., S.W. and L.Z.; L.N. conducted all the proteomic analyses under the direction of J.C. and wrote parts of the manuscript; K.O. conducted the metabolomic analyses with the support of M.V.P.; M.C. conducted the data analysis of CRISPR-Cas9 screening under the direction of T.H.; M.J.Y. performed histopathological analysis; D.D.B. provided WAVE2 constructs and guided actin cytoskeleton-related experiments. B.G. and J.C. acquired the funding support and supervised the study; J.C. reviewed and edited the manuscript; all authors commented on the manuscript.
These authors contributed equally to this work.
Author Contributions
ISSN:1465-7392
1476-4679
DOI:10.1038/s41556-023-01091-2