Sublethal disulfide stress facilitates TLR2-dependent NLRP3 inflammasome activation and pyroptosis in leukemia cells.
8 affiliations
- 1Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
- 2Division of Transcriptional Control and Engineering, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
- 3Molecular Genetics, Graduate School of Medical Sciences, Kanazawa University, Takara-machi, Kanazawa, Japan.
- 4Division of Immune Environment Dynamics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
- 5Immune Network Research Unit, Pursuit of Truth Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
- 6Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Japan. [email protected].
- 7Division of Transcriptional Control and Engineering, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Japan. [email protected].
- 8Cancer-Immune System Interactions Unit, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. [email protected].
Abstract
Inflammasomes are innate immune signaling platforms that activate caspase-1, which in turn cleaves gasdermin D (GSDMD) into its mature form, leading to pyroptosis, an inflammatory form of regulated necrosis. It has been reported that bacterial lipopeptides (BLPs) trigger pyroptosis through NLRP7 inflammasome activation. However, the underlying recognition mechanism remains entirely unclear, and the concept of BLP sensing by NLRP7 has not been well established. In this study, we sought to elucidate the mechanism by which BLPs induce inflammasome activation and pyroptosis in human acute myeloid leukemia cell lines. Through comprehensive analyses, we demonstrate that BLPs induce GSDMD-dependent pyroptosis not via the NLRP7 inflammasome, but through the NLRP3 inflammasome without the need for additional stimuli. Addition of KCl to the culture medium significantly suppressed BLP-induced pyroptosis, suggesting the involvement of K⁺ efflux in inflammasome activation. However, BLPs alone are generally thought to be insufficient to directly induce K⁺ efflux, and K⁺ channel inhibitors had minimal effects, prompting us to hypothesize that K⁺ efflux might result from sublethal membrane damage associated with a distinct cell death mechanism. Among several cell death inhibitors tested, reducing agents, inhibitors of disulfidptosis, which is necrotic cell death caused by excessive disulfide bonding in the actin cytoskeleton, markedly attenuated BLP-induced K⁺ efflux and pyroptosis. Consistent with this, BLP stimulation led to NADPH depletion and increased disulfide bond formation in β-actin, hallmarks of disulfidptosis. These findings suggest that disulfide stress contributes to NLRP3 inflammasome activation and pyroptosis triggered by BLPs in leukemia cells. To our knowledge, this is the first report linking disulfidptosis-associated disulfide stress to innate immune signaling, providing a conceptual framework for exploiting pyroptosis induction in leukemia cells.
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BibTeX
@article{hosojima2026sublethal,
title = {{Sublethal disulfide stress facilitates TLR2-dependent NLRP3 inflammasome activation and pyroptosis in leukemia cells.}},
author = {Shoko Hosojima and Shenghui Zhi and Yamato Tanabe and Takeshi Kinoshita and Takayuki Hoshii and Takashi Suda and Kohsuke Tsuchiya},
journal = {Cell death \& disease},
year = {2026},
month = aug,
doi = {10.1038/s41419-026-09164-4},
url = {https://europepmc.org/article/MED/42957645},
note = {CC BY},
}
RIS
TY - JOUR
TI - Sublethal disulfide stress facilitates TLR2-dependent NLRP3 inflammasome activation and pyroptosis in leukemia cells.
AU - Shoko Hosojima
AU - Shenghui Zhi
AU - Yamato Tanabe
AU - Takeshi Kinoshita
AU - Takayuki Hoshii
AU - Takashi Suda
AU - Kohsuke Tsuchiya
PY - 2026
DA - 2026/08/01
JO - Cell death & disease
DO - 10.1038/s41419-026-09164-4
UR - https://europepmc.org/article/MED/42957645
AB - Inflammasomes are innate immune signaling platforms that activate caspase-1, which in turn cleaves gasdermin D (GSDMD) into its mature form, leading to pyroptosis, an inflammatory form of regulated necrosis. It has been reported that bacterial lipopeptides (BLPs) trigger pyroptosis through NLRP7 inflammasome activation. However, the underlying recognition mechanism remains entirely unclear, and the concept of BLP sensing by NLRP7 has not been well established. In this study, we sought to elucidate the mechanism by which BLPs induce inflammasome activation and pyroptosis in human acute myeloid leukemia cell lines. Through comprehensive analyses, we demonstrate that BLPs induce GSDMD-dependent pyroptosis not via the NLRP7 inflammasome, but through the NLRP3 inflammasome without the need for additional stimuli. Addition of KCl to the culture medium significantly suppressed BLP-induced pyroptosis, suggesting the involvement of K⁺ efflux in inflammasome activation. However, BLPs alone are generally thought to be insufficient to directly induce K⁺ efflux, and K⁺ channel inhibitors had minimal effects, prompting us to hypothesize that K⁺ efflux might result from sublethal membrane damage associated with a distinct cell death mechanism. Among several cell death inhibitors tested, reducing agents, inhibitors of disulfidptosis, which is necrotic cell death caused by excessive disulfide bonding in the actin cytoskeleton, markedly attenuated BLP-induced K⁺ efflux and pyroptosis. Consistent with this, BLP stimulation led to NADPH depletion and increased disulfide bond formation in β-actin, hallmarks of disulfidptosis. These findings suggest that disulfide stress contributes to NLRP3 inflammasome activation and pyroptosis triggered by BLPs in leukemia cells. To our knowledge, this is the first report linking disulfidptosis-associated disulfide stress to innate immune signaling, providing a conceptual framework for exploiting pyroptosis induction in leukemia cells.
SN - 2041-4889
ER -