Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1

Robert Kleemann, Angelika Hausser, Georg Geiger, Ralf Mischke, Anke Burger-Kentischer, Oliver Flieger, Franz-Josef Johannes, Thierry Roger, Thierry Calandra, Aphrodite Kapurniotu, Matthias Grell, Doris Finkelmeier, Herwig Brunner and Jürgen Bernhagen ()
Additional contact information
Robert Kleemann: Laboratory of Biochemistry/Institute for Interfacial Engineering
Angelika Hausser: Institute for Cell Biology and Immunology, University of Stuttgart
Georg Geiger: Laboratory of Biochemistry/Institute for Interfacial Engineering
Ralf Mischke: Laboratory of Biochemistry/Institute for Interfacial Engineering
Anke Burger-Kentischer: Laboratory of Biochemistry/Institute for Interfacial Engineering
Oliver Flieger: Laboratory of Biochemistry/Institute for Interfacial Engineering
Franz-Josef Johannes: Fraunhofer IGB
Thierry Roger: Division of Infectious Diseases Centre Hospitalier Universitaire Vaudois
Thierry Calandra: Division of Infectious Diseases Centre Hospitalier Universitaire Vaudois
Aphrodite Kapurniotu: Physiological-chemical Institute, University of Tübingen
Matthias Grell: Institute for Cell Biology and Immunology, University of Stuttgart
Doris Finkelmeier: Laboratory of Biochemistry/Institute for Interfacial Engineering
Herwig Brunner: Laboratory of Biochemistry/Institute for Interfacial Engineering
Jürgen Bernhagen: Laboratory of Biochemistry/Institute for Interfacial Engineering

Nature, 2000, vol. 408, issue 6809, 211-216

Abstract: Abstract Cytokines are multifunctional mediators that classically modulate immune activity by receptor-mediated pathways. Macrophage migration inhibitory factor (MIF) is a cytokine that has a critical role in several inflammatory conditions1,2,3 but that also has endocrine4,5 and enzymatic functions6,7. The molecular targets of MIF action have so far remained unclear. Here we show that MIF specifically interacts with an intracellular protein, Jab1, which is a coactivator of AP-1 transcription8,9 that also promotes degradation of the cyclin-dependent kinase inhibitor p27Kip1 (ref. 10). MIF colocalizes with Jab1 in the cytosol, and both endogenous and exogenously added MIF following endocytosis bind Jab1. MIF inhibits Jab1- and stimulus-enhanced AP-1 activity, but does not interfere with the induction of the transcription factor NFκB. Jab1 activates c-Jun amino-terminal kinase (JNK) activity and enhances endogenous phospho-c-Jun levels, and MIF inhibits these effects. MIF also antagonizes Jab1-dependent cell-cycle regulation by increasing p27Kip1 expression through stabilization of p27Kip1 protein. Consequently, Jab1-mediated rescue of fibroblasts from growth arrest is blocked by MIF. Amino acids 50–65 and Cys 60 of MIF are important for Jab1 binding and modulation. We conclude that MIF may act broadly to negatively regulate Jab1-controlled pathways and that the MIF–Jab1 interaction may provide a molecular basis for key activities of MIF.

Date: 2000
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DOI: 10.1038/35041591

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