S-Nitrosylation of mitochondrial caspases.
Caspase-3 is a cysteine protease located in both the cytoplasm and mitochondrial intermembrane space that is a central effector of many apoptotic pathways. In resting cells, a subset of caspase-3 zymogens is S-nitrosylated at the active site cysteine, inhibiting enzyme activity. During Fas-induced apoptosis, caspases are denitrosylated, allowing the catalytic site to function. In the current studies, we sought to identify the subpopulation of caspases that is regulated by S-nitrosylation. We report that the majority of mitochondrial, but not cytoplasmic, caspase-3 zymogens contain this inhibitory modification. In addition, the majority of mitochondrial caspase-9 is S-nitrosylated. These studies suggest that S-nitrosylation plays an important role in regulating mitochondrial caspase function and that the S-nitrosylation state of a given protein depends on its subcellular localization.
Mannick
J B
JB
Department of Medicine, University of Massachusetts Medical School, Shrewsbury, MA 01545, USA. joan.mannick@umassmed.edu
Schonhoff
C
C
Papeta
N
N
Ghafourifar
P
P
Szibor
M
M
Fang
K
K
Gaston
B
B
D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D021382:Protein Sorting Signals; D021381:Protein Transport; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000494:pharmacology
D004792:Enzyme Precursors; D021382:Protein Sorting Signals; D019014:fas Receptor; D019001:Nitric Oxide Synthase; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases