CD74 is a cell surface receptor, but is better known as the human histocompatibility leukocyte antigen (HLA) class ll-assoociated invariant chain that transports class II from the endoplasmic reticulum to vesicles which fuse with endosomes. The physiological role for the presence of CD74 on the cell surface is not known. Some experiments show that it is necessary for the rapid uptake of HLA-DR-specific monoclonal antibodies into early endosomes and for peptide loading on the cell surface, but cell-surface CD74 does not always correlate with cell-surface expression of HLA class II molecules. More recently, CD74 has been identified as a cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF). MIF is a pro-inflammatory protein that is secreted by cells upon exposure to microbes or their products. Increased levels of this protein have been shown to mediate lethality in mice models of acute inflammation (endotoxemia) and septic shock (cecal ligation and puncture). Inhibition of MIF shows therapeutic benefits in animal models of arthritis, acute colitis, acute infections, and multiple forms of cancer. In humans, high levels of MIF are associated with these diseases. The hypothesis of this proposal is that CD74 mediates the biological effects of MIF. This proposal aims to (1) examine the requirement for CD74 in various signaling pathways responsible for MIF biology (MAP kinase cytoplasmic PLA2 activation, expression and activation of COX-2, expression of Toll-like receptor 4, counter-regulation of glucocorticoid anti-inflammatory effects, inhibition of p53), (2) characterize any potential relationship between the MIF catalytic site and CD74 binding, (3) characterize the three dimensional structure of the complex between MIF and the ectodomain of CD74 (sCD74), and (4) use site-directed and structure-based mutagenesis to determine residues on MIF and CD74 that are important for binding and/or signaling. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-III-F (01))
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Gondre-Lewis, Timothy A
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Yale University
Schools of Medicine
New Haven
United States
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Pantouris, Georgios; Bucala, Richard; Lolis, Elias J (2018) Structural Plasticity in the C-Terminal Region of Macrophage Migration Inhibitory Factor-2 Is Associated with an Induced Fit Mechanism for a Selective Inhibitor. Biochemistry 57:3599-3605
Pantouris, Georgios; Ho, Junming; Shah, Dilip et al. (2018) Nanosecond Dynamics Regulate the MIF-Induced Activity of CD74. Angew Chem Int Ed Engl 57:7116-7119
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Pantouris, Georgios; Rajasekaran, Deepa; Garcia, Alvaro Baeza et al. (2014) Crystallographic and receptor binding characterization of Plasmodium falciparum macrophage migration inhibitory factor complexed to two potent inhibitors. J Med Chem 57:8652-6
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Fan, Chengpeng; Rajasekaran, Deepa; Syed, Mansoor Ali et al. (2013) MIF intersubunit disulfide mutant antagonist supports activation of CD74 by endogenous MIF trimer at physiologic concentrations. Proc Natl Acad Sci U S A 110:10994-9
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