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* Yale University School of Medicine, New Haven, CT 06520;
Department of Biochemistry and Molecular Cell Biology, University Hospital RWTH, Aachen, Germany;
University College Dublin, School of Medicine, Dublin, Ireland;
Heidelberg University Biochemistry Center (BZH), Heidelberg, Germany; and
¶ University of Louisville, Louisville, KY 40202
Macrophage migration inhibitory factor (MIF) is a leaderless protein that is secreted from cells by a specialized, nonclassical export pathway. The release of MIF nevertheless is regulated and its production in response to different inflammatory, mitogenic, and hormonal stimuli plays an important role in diverse physiologic and pathologic processes. We report herein the identification of the Golgi complex-associated protein p115 as an intracellular binding partner for MIF. MIF interacts with p115 in the cytoplasm and the stimulated secretion of MIF results in the accumulation of both proteins in supernatants, which is consistent with MIF release from cells in conjunction with p115. The depletion of p115 from monocytes/macrophages decreases the release of MIF but not other cytokines following inflammatory stimulation or intracellular bacterial infection. Notably, the small molecule MIF inhibitor 4-iodo-6-phenylpyrimidine inhibits MIF secretion by targeting the interaction between MIF and p115. These data reveal p115 to be a critical intermediary component in the regulated secretion of MIF from monocytes/macrophages.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Health (to L.L., R.B., and P.B.K.), Deutsche Forschungsgemeinschaft Grant SFB542/A7 (to J.B.), and fellowships from the Studienstiftung des Deutschen Volkes (to M.M.) and the German Academic Exchange Service (Deutscher Akademischer Austauschdienst) (to S.Z.).
2 Current address: Department of Internal Medicine, Kangwon National University School of Medicine, 1 Kangwondaehak-gil, Chuncheon-Si, Gangwondo, 200-701 South Korea.
3 Address correspondence and reprint requests to Dr. Richard Bucala, Yale University School of Medicine, TAC S525, PO Box 208031, 300 Cedar Street, New Haven, CT 06520-8031. E-mail address: Richard.Bucala{at}Yale.edu
4 Abbreviations used in this paper: MIF, migration inhibitory factor; FGF, fibroblast growth factor; 4-IPP, 4-iodo-6-phenylpyrimidine; ISO-1, (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester; MOI, multiplicity of infection; NAPQI, N-acetyl-p-benzoquinone imine; PIP-K, phosphatidylinositol phosphate kinase; siRNA, short interfering RNA; ER, endoplasmic reticulum; RNAi, RNA interference; shRNA, short hairpin RNA; LDH, lactate dehydrogenase.
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