Journal
JOURNAL OF CELL BIOLOGY
Volume 161, Issue 3, Pages 507-519Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200211104
Keywords
calcineurin; I kappa B beta; mitochondrial stress signaling; dephosphorylation; NF kappa B/Rel activation
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Funding
- NCI NIH HHS [R37 CA022762, R01 CA022762, CA-22762] Funding Source: Medline
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Mitochondrial genetic and metabolic stress causes activation of calcineurin (Cn), NFAT, ATF2, and NFkappaB/Rel factors, which collectively alter the expression of an array of nuclear genes. We demonstrate here that mitochondrial stress-induced activation of NFkappaB/Rel factors involves inactivation Of IkappaBbeta through Cn-mediated dephosphorylation. Phosphorylated IkappaBbeta is a substrate for Cn phosphatase, which was inhibited by FK506 and RII peptide. Chemical cross-linking and coimmunoprecipitation show that NFkappaB/Rel factor-bound IkappaBbeta forms a ternary complex with Cn under in vitro and in vivo conditions that was sensitive to FK506. Results show that phosphorylation at S313 and S315 from the COOH-terminal PEST domain Of IkappaBbeta is critical for binding to Cn. Mutations at S313/S315 Of IkappaBbeta abolished Cn binding, inhibited Cn-mediated increase of Rel proteins in the nucleus, and had a dominant-negative effect on the mitochondrial stress-induced expression of RyR1 and cathepsin L genes. Our results show the distinctive nature of mitochondrial stress-induced NFkappaB/Rel activation, which is independent of IKKalpha and IKKbeta kinases and affects gene target(s) that are different from cytokine and TNFalpha-induced stress signaling. The results provide new insights into the role of Cn as a critical link between Ca2+ signaling and NFkappaB/Rel activation.
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