Tyk2 tyrosine kinase expression is required for the maintenance of mitochondrial respiration in primary pro-B lymphocytes.
Tyk2, a member of the Jak family of protein tyrosine kinases, is critical for the biological actions of alpha/beta interferon (IFN-alpha/beta). 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-beta. 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-beta. 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.
Potla
Ramesh
R
Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Koeck
Thomas
T
Wegrzyn
Joanna
J
Cherukuri
Srujana
S
Shimoda
Kazuya
K
Baker
Darren P
DP
Wolfman
Janice
J
Planchon
Sarah M
SM
Esposito
Christine
C
Hoit
Brian
B
Dulak
Jozef
J
Wolfman
Alan
A
Stuehr
Dennis
D
Larner
Andrew C
AC
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000201:enzymology / Q000502:physiology*; D019069:Cell Respiration; D002478:Cells, Cultured; D004579:Electron Transport / Q000235:genetics; D007155:Immunologic Factors / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000502:physiology*; D008954:Models, Biological; D010805:Physical Conditioning, Animal; D015398:Signal Transduction; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014162:Transfection
D007155:Immunologic Factors; D016899:Interferon-beta; D000255:Adenosine Triphosphate; D053634:TYK2 Kinase