Heat shock protein 75 (TRAP1) antagonizes reactive oxygen species generation and protects cells from granzyme M-mediated apoptosis.
Natural killer (NK) cells play an important role in innate immunity against virally infected or transformed cells as the first defense line. Granzyme M (GzmM) is an orphan granzyme that is constitutively highly expressed in NK cells and is consistent with NK cell-mediated cytolysis. We recently demonstrated that GzmM induces caspase-dependent apoptosis with DNA fragmentation through direct cleavage of inhibitor of caspase-activated DNase (ICAD). However, the molecular mechanisms for GzmM-induced apoptosis are unclear. We found GzmM causes mitochondrial swelling and loss of mitochondrial transmembrane potential. Moreover, GzmM initiates reactive oxygen species (ROS) generation and cytochrome c release. Heat shock protein 75 (HSP75, also known as TRAP1) acts as an antagonist of ROS and protects cells from GzmM-mediated apoptosis. GzmM cleaves TRAP1 and abolishes its antagonistic function to ROS, resulting in ROS accumulation. Silencing TRAP1 through RNA interference increases ROS accumulation, whereas TRAP1 overexpression attenuates ROS production. ROS accumulation is in accordance with the release of cytochrome c from mitochondria and enhances GzmM-mediated apoptosis.
Hua
Guoqiang
G
National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
Zhang
Qixiang
Q
Fan
Zusen
Z
D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D020169:Caspases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045304:Cytochromes c / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053938:DNA Fragmentation; D053804:Granzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000235:genetics / Q000276:immunology; D008928:Mitochondria / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D018841:HSP90 Heat-Shock Proteins; D017382:Reactive Oxygen Species; C092306:TRAP1 protein, human; D045304:Cytochromes c; C509218:GZMM protein, human; D053804:Granzymes; D020169:Caspases