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Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis

Open access
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·2023·Nature Cell Biology
DOI 10.1038/s41556-023-01091-2
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Abstract

Liu, Nie et al. identify disulfidptosis as a form of cell death resulting from aberrant accumulation of disulfide bonds in actin cytoskeleton proteins that is induced following glucose starvation and dependent on SLC7A11-mediated cystine uptake. 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^high 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^high 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^high cancer cells and suppress SLC7A11^high 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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Metadata

Authors
Liu, X., Nie, L., Zhang, Y., Yan, Y., Wang, C., Colic, M., Olszewski, K., Horbath, A., Chen, X., Lei, G., Mao, C., Wu, S., Zhuang, L., Poyurovsky, M. V., James You, M., Hart, T., Billadeau, D. D., Chen, J., & Gan, B.
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2023-02-06
Volume
25
Issue
3
Pages
404-414
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/s41556-023-01091-2
OpenAlex
W4319310752
Cited by
1,132
References
5
FWCI
183.16
Type
journal article
Language
en
Open access
green
Licence
Funders
Foundation for the National Institutes of Health (R35GM130119, R01DK107733, R01CA244144, R01CA247992)

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CoChat. (2026). Citation check: Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. https://app.cochat.ai/papers/10.1038/s41556-023-01091-2
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Liu, X., Nie, L., Zhang, Y., Yan, Y., Wang, C., Colic, M., Olszewski, K., Horbath, A., Chen, X., Lei, G., Mao, C., Wu, S., Zhuang, L., Poyurovsky, M. V., James You, M., Hart, T., Billadeau, D. D., Chen, J., & Gan, B. (2023). Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. Nature Cell Biology. https://doi.org/10.1038/s41556-023-01091-2

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