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Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death

Dykxhoorn, Derek M.
Ferrini, Roger
Lieberman, Judy
Published in Cell. 2008, vol. 133, no. 4, p. 681-692
Abstract The killer lymphocyte protease granzyme A (GzmA) triggers caspase-independent target cell death with morphological features of apoptosis. We previously showed that GzmA acts directly on mitochondria to generate reactive oxygen species (ROS) and disrupt the transmembrane potential (DeltaPsi(m)) but does not permeabilize the mitochondrial outer membrane. Mitochondrial damage is critical to GzmA-induced cell death since cells treated with superoxide scavengers are resistant to GzmA. Here we find that GzmA accesses the mitochondrial matrix to cleave the complex I protein NDUFS3, an iron-sulfur subunit of the NADH:ubiquinone oxidoreductase complex I, after Lys56 to interfere with NADH oxidation and generate superoxide anions. Target cells expressing a cleavage site mutant of NDUFS3 are resistant to GzmA-mediated cell death but remain sensitive to GzmB.
Keywords Animals*Cell Death/drug effectsCell-Free SystemGranzymes/genetics/*metabolismHSP70 Heat-Shock Proteins/metabolismHSP90 Heat-Shock Proteins/metabolismHeLa CellsHumansLiver/cytologyMembrane Potential, MitochondrialMiceMitochondria/*chemistry/*metabolismNADH Dehydrogenase/metabolismOxidoreductases/metabolismProtein TransportReactive Oxygen Species/metabolismRecombinant Proteins/metabolismRotenone/pharmacologyT-Lymphocytes, Cytotoxic/enzymologyUncoupling Agents/pharmacology
PMID: 18485875
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Research group ROS in CTL mediated cell death : from mechanism to applications (898)
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MARTINVALET, Denis et al. Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death. In: Cell, 2008, vol. 133, n° 4, p. 681-692. https://archive-ouverte.unige.ch/unige:19073

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Deposited on : 2012-03-27

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