Pancortin-2 interacts with WAVE1 and Bcl-xL in a mitochondria-associated protein complex that mediates ischemic neuronal death.
The actin-modulating protein Wiskott-Aldrich syndrome protein verprolin homologous-1 (WAVE1) and a novel CNS-specific protein, pancortin, are highly enriched in adult cerebral cortex, but their functions are unknown. Here we show that WAVE1 and pancortin-2 interact in a novel cell death cascade in adult, but not embryonic, cerebral cortical neurons. Focal ischemic stroke induces the formation of a protein complex that includes pancortin-2, WAVE1, and the anti-apoptotic protein Bcl-xL. The three-protein complex is associated with mitochondria resulting in increased association of Bax with mitochondria, cytochrome c release, and neuronal apoptosis. In pancortin null mice generated using a Cre-loxP system, ischemia-induced WAVE1-Bcl-xL interaction is diminished, and cortical neurons in these mice are protected against ischemic injury. Thus, pancortin-2 is a mediator of ischemia-induced apoptosis of neurons in the adult cerebral cortex and functions in a novel mitochondrial/actin-associated protein complex that sequesters Bcl-xL.
Cheng
Aiwu
A
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224, USA.
Arumugam
Thiruma V
TV
Liu
Dong
D
Khatri
Rina G
RG
Mustafa
Khadija
K
Kwak
Seung
S
Ling
Huai-Ping
HP
Gonzales
Cathleen
C
Xin
Ouyang
O
Jo
Dong-Gyu
DG
Guo
Zhihong
Z
Mark
Robert J
RJ
Mattson
Mark P
MP
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002545:Brain Ischemia / Q000235:genetics / Q000473:pathology*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D045304:Cytochromes c; D004622:Embryo, Mammalian; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000502:physiology*; D007839:Functional Laterality; D006023:Glycoproteins / Q000172:deficiency / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C492303:Wasf2 protein, mouse; D051300:Wiskott-Aldrich Syndrome Protein Family; D051020:bcl-X Protein; C081451:olfactomedin; D049452:Green Fluorescent Proteins; D045304:Cytochromes c