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 gasderm...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 ^(1)H-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.展开更多
基金supported by grants from the National Natural Science Foundation of China(92253303,U25A20105 and 82021003 to Q.W.,U23A20450 to H.Z.C.)the Ministry of Science and Technology of China(2020YFA0803403 to Q.W.)+1 种基金the Natural Science Foundation of Fujian Province,China(2024J01021 to H.Z.C.)the Wang Deyao Outstanding Graduate Scholarship Program of Xiamen University,China(to L.Z.W.,Y.Y.H.and H.J.H.).
文摘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 ^(1)H-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.
