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Molecular and Cellular Biology, November 2006, p. 8562-8571, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00497-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Tyk2 Tyrosine Kinase Expression Is Required for the Maintenance of Mitochondrial Respiration in Primary Pro-B Lymphocytes{triangledown}

Ramesh Potla,1,2,{dagger} Thomas Koeck,3,{dagger} Joanna Wegrzyn,1,4 Srujana Cherukuri,5 Kazuya Shimoda,6 Darren P. Baker,7 Janice Wolfman,5 Sarah M. Planchon,5 Christine Esposito,8 Brian Hoit,9 Jozef Dulak,4 Alan Wolfman,5 Dennis Stuehr,2,3 and Andrew C. Larner1,2*

Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195,1 Department of Biology, Cleveland State University, Cleveland, Ohio 44114,2 Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195,3 Department of Medical Biotechnology, Faculty of Biotechnology, Jagiellonian University, Krakow, Poland,4 Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195,5 Medicine and Biosystemic Science, Kyushu University, Fukuoka, Japan,6 Biogen Idec Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142,7 Department of Medicine, Cardiology Section, Louis Stokes VA Medical Center, Cleveland, Ohio 44106,8 Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 441069

Received 21 March 2006/ Returned for modification 21 April 2006/ Accepted 17 August 2006

Tyk2, a member of the Jak family of protein tyrosine kinases, is critical for the biological actions of alpha/beta interferon (IFN-{alpha}/ß). Although Tyk2–/– mice are phenotypically normal, they exhibit abnormal responses to inflammatory challenges in a variety of cells isolated from Tyk2–/– mice. The reported phenotypic alterations in both Tyk2-null cells and mice are consistent with the possibility that the expression of this tyrosine kinase may regulate mitochondrial function. We report here that Tyk2-null pro-B cells are markedly deficient in basal oxygen consumption and exhibit a significant decrease in steady-state cellular ATP levels compared to wild-type cells. Tyk2-null cells also exhibit impaired complex I, III, and IV function of the mitochondrial electron transport chain. Reconstitution of Tyk2-null pro-B cells with either the wild type or a kinase-inactive mutant of Tyk2 restores basal mitochondrial respiration. By contrast, the kinase activity of Tyk2 is required for maintenance of both complex I-dependent mitochondrial respiration as well as induction of apoptosis in cells incubated with IFN-ß. Consistent with the role of Tyk2 in the regulation of tyrosine phosphorylation of Stat3, expression of a constitutively active Stat3 can restore the mitochondrial respiration in Tyk2-null cells treated with IFN-ß. Finally, Tyk2–/– mice show decreased exercise tolerance compared to wild-type littermates. Our results implicate a novel role for Tyk2 kinase and Stat3 phosphorylation in mitochondrial respiration.

* Corresponding author. Mailing address: Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Phone: (216) 445-9045. Fax: (216) 444-9329. E-mail: larnera{at}ccf.org.

{triangledown} Published ahead of print on 18 September 2006.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, November 2006, p. 8562-8571, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00497-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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