Oxidative photocatalysis on membranes triggers non-canonical pyroptosis

Chaiheon Lee, Mingyu Park, W. C. Bhashini Wijesinghe, Seungjin Na, Chae Gyu Lee, Eunhye Hwang, Gwangsu Yoon, Jeong Kyeong Lee, Deok-Ho Roh, Yoon Hee Kwon, Jihyeon Yang, Sebastian A. Hughes, James E. Vince, Jeong Kon Seo (), Duyoung Min () and Tae-Hyuk Kwon ()
Additional contact information
Chaiheon Lee: Ulsan National Institute of Science and Technology (UNIST)
Mingyu Park: Ulsan National Institute of Science and Technology (UNIST)
W. C. Bhashini Wijesinghe: Ulsan National Institute of Science and Technology (UNIST)
Seungjin Na: Korea Basic Science Institute
Chae Gyu Lee: Ulsan National Institute of Science and Technology (UNIST)
Eunhye Hwang: Ulsan National Institute of Science and Technology (UNIST)
Gwangsu Yoon: Ulsan National Institute of Science and Technology (UNIST)
Jeong Kyeong Lee: Ulsan National Institute of Science and Technology (UNIST)
Deok-Ho Roh: Ulsan National Institute of Science and Technology (UNIST)
Yoon Hee Kwon: O2MEDi inc.
Jihyeon Yang: O2MEDi inc.
Sebastian A. Hughes: The Walter and Eliza Hall Institute of Medical Research
James E. Vince: The Walter and Eliza Hall Institute of Medical Research
Jeong Kon Seo: O2MEDi inc.
Duyoung Min: Ulsan National Institute of Science and Technology (UNIST)
Tae-Hyuk Kwon: Ulsan National Institute of Science and Technology (UNIST)

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Intracellular membranes composing organelles of eukaryotes include membrane proteins playing crucial roles in physiological functions. However, a comprehensive understanding of the cellular responses triggered by intracellular membrane-focused oxidative stress remains elusive. Herein, we report an amphiphilic photocatalyst localised in intracellular membranes to damage membrane proteins oxidatively, resulting in non-canonical pyroptosis. Our developed photocatalysis generates hydroxyl radicals and hydrogen peroxides via water oxidation, which is accelerated under hypoxia. Single-molecule magnetic tweezers reveal that photocatalysis-induced oxidation markedly destabilised membrane protein folding. In cell environment, label-free quantification reveals that oxidative damage occurs primarily in membrane proteins related to protein quality control, thereby aggravating mitochondrial and endoplasmic reticulum stress and inducing lytic cell death. Notably, the photocatalysis activates non-canonical inflammasome caspases, resulting in gasdermin D cleavage to its pore-forming fragment and subsequent pyroptosis. These findings suggest that the oxidation of intracellular membrane proteins triggers non-canonical pyroptosis.

Date: 2024
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DOI: 10.1038/s41467-024-47634-5

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