A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis.
Apaf1/CED4 family members play central roles in apoptosis regulation as activators of caspase family cell death proteases. These proteins contain a nucleotide-binding (NB) self-oligomerization domain and a caspase recruitment domain (CARD). A novel human protein was identified, NAC, that contains an NB domain and CARD. The CARD of NAC interacts selectively with the CARD domain of Apaf1, a caspase-activating protein that couples mitochondria-released cytochrome c (cyt-c) to activation of cytosolic caspases. Cyt-c-mediated activation of caspases in cytosolic extracts and in cells is enhanced by overexpressing NAC and inhibited by reducing NAC using antisense/DNAzymes. Furthermore, association of NAC with Apaf1 is cyt c-inducible, resulting in a mega-complex (>1 MDa) containing both NAC and Apaf1 and correlating with enhanced recruitment and proteolytic processing of pro-caspase-9. NAC also collaborates with Apaf1 in inducing caspase activation and apoptosis in intact cells, whereas fragments of NAC representing only the CARD or NB domain suppress Apaf1-dependent apoptosis induction. NAC expression in vivo is associated with terminal differentiation of short lived cells in epithelia and some other tissues. The ability of NAC to enhance Apaf1-apoptosome function reveals a novel paradigm for apoptosis regulation.
Chu
Z L
ZL
Burnham Institute, La Jolla, California 92037, USA.
Pio
F
F
Xie
Z
Z
Welsh
K
K
Krajewska
M
M
Krajewski
S
S
Godzik
A
A
Reed
J C
JC
D000595:Amino Acid Sequence; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D001483:Base Sequence; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D003574:Cytochrome c Group / Q000378:metabolism*; D017931:DNA Primers; D004742:Enhancer Elements, Genetic; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D003574:Cytochrome c Group; D017931:DNA Primers; D011506:Proteins; D020169:Caspases