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PMID: 12732617 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Mitochondria to nucleus stress signaling: a distinctive mechanism of NFkappaB/Rel activation through calcineurin-mediated inactivation of IkappaBbeta.

The Journal of cell biology ·Vol. 161 ·No. 3 ·2003-05-12 ·Pages 507-19

Biswas G, Anandatheerthavarada HK, Zaidi M, Avadhani NG

Abstract

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.

MeSH Terms
Animals Binding Sites/drug effects,genetics Calcineurin/genetics,metabolism Calcium Signaling/drug effects,genetics Cell Nucleus/drug effects,metabolism Cells, Cultured Enzyme Inhibitors/pharmacology Eukaryotic Cells/drug effects,metabolism I-kappa B Proteins/genetics,metabolism Mice Mitochondria/drug effects,metabolism Mutation/genetics NF-kappa B/genetics,metabolism Oncogene Proteins v-rel/genetics,metabolism Phosphoprotein Phosphatases/antagonists & inhibitors,metabolism Phosphorylation/drug effects Protein Structure, Tertiary/drug effects,genetics Serine/metabolism Stress, Physiological/genetics,metabolism Tumor Necrosis Factor-alpha/metabolism,pharmacology Up-Regulation/drug effects,genetics
Chemicals
Enzyme Inhibitors I kappa B beta protein I-kappa B Proteins NF-kappa B Oncogene Proteins v-rel Tumor Necrosis Factor-alpha Serine Calcineurin Phosphoprotein Phosphatases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Biswas Gopa
Dept. of Animal Biology, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Anandatheerthavarada Hindupur K
Zaidi Mone
Avadhani Narayan G
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200211104
Published
2003-05-12
Epub
2003-00-05
Pages
507-19
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2172940
Subset
IM
Grants
NCI NIH HHS · R01 CA022762 · United States
NCI NIH HHS · R37 CA022762 · United States
NCI NIH HHS · CA-22762 · United States
External Links
PubMed source DOI: 10.1083/jcb.200211104 PMC Full Text View journal details
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