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© The Rockefeller University Press, 0021-9525/2003/5/507 $5.00
The Journal of Cell Biology, Volume 161, Number 3, 507-519

Mitochondria to nucleus stress signaling

: a distinctive mechanism of NFB/Rel activation through calcineurin-mediated inactivation of IBß

Gopa Biswas¹, Hindupur K. Anandatheerthavarada¹, Mone Zaidi² and Narayan G. Avadhani¹

¹ The Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
² Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, and Bronx VA Geriatric Research Education and Medical Center, New York, NY 10029

Address correspondence to Narayan G. Avadhani, Dept. of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104. Tel.: (215) 898-8819. Fax: (215) 573-6651. E-mail: narayan{at}vet.upenn.edu

Mitochondrial genetic and metabolic stress causes activation of calcineurin (Cn), NFAT, ATF2, and NFB/Rel factors, which collectively alter the expression of an array of nuclear genes. We demonstrate here that mitochondrial stress–induced activation of NFB/Rel factors involves inactivation of IBß through Cn-mediated dephosphorylation. Phosphorylated IBß is a substrate for Cn phosphatase, which was inhibited by FK506 and RII peptide. Chemical cross-linking and coimmunoprecipitation show that NFB/Rel factor–bound IBß 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 IBß is critical for binding to Cn. Mutations at S313/S315 of IBß 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 NFB/Rel activation, which is independent of IKK and IKKß kinases and affects gene target(s) that are different from cytokine and TNF-induced stress signaling. The results provide new insights into the role of Cn as a critical link between Ca²⁺ signaling and NFB/Rel activation.

Key Words: calcineurin; IBß; mitochondrial stress signaling; dephosphorylation; NFKB/Rel activation

^* Abbreviations used in this paper: _m, mitochondrial membrane potential; CCCP, carbonyl cyanide-m chlorophenylhydrazone; Cn, calcineurin; DSP, dithiobis(succinimidylpropionate); LMB, leptomycin B; mtDNA, mitochondrial DNA.

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