Protective role of Cop in Rip2/caspase-1/caspase-4-mediated HeLa cell death.
CARD only protein (Cop) was recently identified as a protein with significant homology with the CARD of caspase-1. We have conducted functional studies on Cop and report on its role as an inhibitor of cell death in a broad range of cell death paradigms. A notable exception in the ability of Cop to inhibit cell death pertains to its inability to inhibit ER stress-mediated cell death. Furthermore, in addition to the known interaction of Cop and caspase-1, we demonstrated a novel interaction of Cop with caspase-4. We propose that Cop's action to prevent TNF-alpha-induced cell death may operate independently of the mitochondrial death pathway. Furthermore, Cop overexpression inhibits Bid cleavage. In summary, Cop inhibition of cell death, at least to a certain extent, results from its interference with the activation of caspase-1 and caspase-4. Understanding the mechanistic details modulating caspase cell death pathways should provide important information for the development of therapies for diseases featuring aberrant caspase activation. Cop, as an inhibitor of an important apical caspase cell death axis, may provide a tool for modulating pathological cell death.
Wang
Xin
X
Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, LMRC 123, Boston, MA 02115, USA.
Narayanan
Malini
M
Bruey
Jean-Marie
JM
Rigamonti
Dorotea
D
Cattaneo
Elena
E
Reed
John C
JC
Friedlander
Robert M
RM
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D020170:Caspase 1 / Q000737:chemistry / Q000378:metabolism*; D020169:Caspases / Q000737:chemistry / Q000378:metabolism*; D053471:Caspases, Initiator; D016923:Cell Death; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism*
D002352:Carrier Proteins; D007375:Interleukin-1; C436144:LLID-114769 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; C093516:CASP4 protein, human; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1