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Disruption of heme homeostasis by nuclear receptor Nur77 induces pyroptosis through granzyme B-dependent GSDMC
Liu-Zheng Wu1, Ya-Ying Huang1, Hai-Jing Hu1
1State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
Abstract:
Pyroptosis plays a crucial role in physiological and pathological processes. As melanoma cells are resistant to apoptosis but express gasdermin proteins, it is appealing to counter melanoma with the induction of gasdermin-executed pyroptosis. GSDMC, initially cloned from metastatic melanoma cells, has been demonstrated as a potential executioner of pyroptosis. However, no lead compounds that trigger GSDMC-mediated pyroptosis have been reported, which limits the in-depth investigation of GSDMC functions. Here, we discovered a chemical compound, dodecyl 1H-benzo[d]imidazole-5-carboxylate (DdBIC), that targeted the nuclear receptor Nur77 to induce pyroptosis through cleaving GSDMC by granzyme B in melanoma cells. Upon DdBIC binding, Nur77 was translocated to the mitochondria to activate the hemoprotein SDHA to overconsume succinyl-CoA, subsequently disrupting the homeostasis of heme in the SDH complex and resulting in electron leakage to induce mito-ROS production. This mito-ROS signal was sensed by the mitochondrial protease OMA1 via oxidation, which led to downstream OPA1 cleavage and subsequent released into the cytoplasm. Cytosolic OPA1 activated PERK to induce the integrated stress response (ISR), which further activated granzyme B to cleave GSDMC, culminating in the induction of pyroptosis. Together, this study elucidates a signal cascade from Nur77-impaired homeostasis of heme metabolism to PERK-mediated ISR activation, and reveals a novel paradigm, by which granzyme B, rather than caspases, cleaves GSDMC for pyroptotic induction and provides a new strategy for the therapeutic treatment of melanoma by lead compound DdBIC.
Insights
We discovered dodecyl 1H-benzo[d]imidazole-5-carboxylate (DdBIC), a compound that triggers GSDMC-mediated pyroptosis in melanoma cells. This novel approach targets the Nur77-heme metabolism-ISR pathway, offering a new strategy for melanoma treatment.
Area of Science:
- Cellular Biology
- Molecular Oncology
- Drug Discovery
Background:
- Melanoma cells resist apoptosis but express gasdermin proteins, making pyroptosis a potential therapeutic target.
- GSDMC is a key executioner of pyroptosis, but compounds that induce GSDMC-mediated pyroptosis are lacking.
- Targeting GSDMC offers a promising strategy to overcome melanoma's resistance to apoptosis.
Purpose of the Study:
- To identify lead compounds that induce GSDMC-mediated pyroptosis in melanoma.
- To elucidate the signaling pathway involved in DdBIC-induced pyroptosis.
- To explore a novel therapeutic strategy for melanoma treatment.
Main Methods:
- Discovery of dodecyl 1H-benzo[d]imidazole-5-carboxylate (DdBIC) as a pyroptosis inducer.
- Investigation of DdBIC's mechanism involving nuclear receptor Nur77 translocation and mitochondrial dysfunction.
- Analysis of the role of heme metabolism, mito-ROS, OMA1, OPA1, PERK, and granzyme B in the pyroptotic pathway.
- Demonstration of GSDMC cleavage by granzyme B, not caspases, leading to pyroptosis.
Main Results:
- DdBIC triggers pyroptosis in melanoma cells by cleaving GSDMC via granzyme B.
- DdBIC induces Nur77 translocation to mitochondria, disrupting heme metabolism and generating mito-ROS.
- The pathway involves OMA1, OPA1, PERK, and the integrated stress response (ISR) leading to granzyme B activation.
- This study reveals a novel caspase-independent GSDMC cleavage mechanism.
Conclusions:
- DdBIC is a novel lead compound for inducing GSDMC-mediated pyroptosis in melanoma.
- The identified pathway highlights a new mechanism of pyroptosis involving Nur77, heme metabolism, and ISR.
- This provides a promising therapeutic strategy for treating melanoma by targeting GSDMC.
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