A distinctive physiological role for IkappaBbeta in the propagation of mitochondrial respiratory stress signaling.
The NFkappaBs regulate an array of physiological and pathological processes, including propagation of mitochondrial respiratory stress signaling in mammalian cells. We showed previously that mitochondrial stress activates NFkappaB using a novel calcineurin-requiring pathway that is different from canonical or non-canonical pathways. This study shows that IkappaBbeta is essential for the propagation of mitochondrial stress signaling. Knock down of IkappaBbeta, but not IkappaBalpha, mRNA reduced the mitochondrial stress-mediated activation and nuclear translocation of cRel:p50, inhibiting expression of nuclear target genes RyR1 and cathepsin L. IkappaBbeta mRNA knock down also reduced resistance to staurosporine-induced apoptosis and decreased in vitro invasiveness. Induced receptor switching to insulin-like growth factor-1 receptor and increased glucose uptake are hallmarks of mitochondrial stress. IkappaBbeta mRNA knock down selectively abrogated the receptor switch and altered tubulin cytoskeletal organization. These results show that mitochondrial stress signaling uses an IkappaBbeta-initiated NFkappaB pathway that is distinct from the other known NFkappaB pathways. Furthermore, our results demonstrate the distinctive physiological roles of the two inhibitory proteins IkappaBbeta and IkappaBalpha.
Biswas
Gopa
G
Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Tang
Weigang
W
Sondheimer
Neal
N
Guha
Manti
M
Bansal
Seema
S
Avadhani
Narayan G
NG
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D019069:Cell Respiration; D002470:Cell Survival; D003599:Cytoskeleton / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D032446:Myoblasts / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D051275:Glucose Transporter Type 4; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D017526:Receptor, IGF Type 1; D019703:Calcineurin; D005947:Glucose; D002118:Calcium