Document Detail


Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death.
MedLine Citation:
PMID:  18485875     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Denis Martinvalet; Derek M Dykxhoorn; Roger Ferrini; Judy Lieberman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Cell     Volume:  133     ISSN:  1097-4172     ISO Abbreviation:  Cell     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-05-19     Completed Date:  2008-06-10     Revised Date:  2014-09-10    
Medline Journal Info:
Nlm Unique ID:  0413066     Medline TA:  Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  681-92     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Death* / drug effects
Cell-Free System
Granzymes / genetics,  metabolism*
HSP70 Heat-Shock Proteins / metabolism
HSP90 Heat-Shock Proteins / metabolism
HeLa Cells
Humans
Liver / cytology
Membrane Potential, Mitochondrial
Mice
Mitochondria / chemistry*,  metabolism*
NADH Dehydrogenase / metabolism
Oxidoreductases / metabolism
Protein Transport
Reactive Oxygen Species / metabolism
Recombinant Proteins / metabolism
Rotenone / pharmacology
T-Lymphocytes, Cytotoxic / enzymology
Uncoupling Agents / pharmacology
Grant Support
ID/Acronym/Agency:
AI45587/AI/NIAID NIH HHS; R01 AI045587/AI/NIAID NIH HHS; R01 AI045587-10/AI/NIAID NIH HHS; T32 HL66987/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/HSP70 Heat-Shock Proteins; 0/HSP90 Heat-Shock Proteins; 0/Reactive Oxygen Species; 0/Recombinant Proteins; 0/Uncoupling Agents; 03L9OT429T/Rotenone; EC 1.-/Oxidoreductases; EC 1.16.-/NADH-vandate oxidoreductase; EC 1.6.5.3/NDUFS3 protein, human; EC 1.6.99.3/NADH Dehydrogenase; EC 3.4.21.-/Granzymes; EC 3.4.21.78/GZMA protein, human
Comments/Corrections
Comment In:
Cell. 2008 May 16;133(4):568-70   [PMID:  18485862 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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