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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI065029-01A1
Application #
7146881
Study Section
Special Emphasis Panel (ZRG1-III-F (01))
Program Officer
Rathbun, Gary
Project Start
2006-06-01
Project End
2011-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
1
Fiscal Year
2006
Total Cost
$412,188
Indirect Cost
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
Lacy, Michael; Kontos, Christos; Brandhofer, Markus et al. (2018) Identification of an Arg-Leu-Arg tripeptide that contributes to the binding interface between the cytokine MIF and the chemokine receptor CXCR4. Sci Rep 8:5171
Rajasekaran, Deepa; Gröning, Sabine; Schmitz, Corinna et al. (2016) Macrophage Migration Inhibitory Factor-CXCR4 Receptor Interactions: EVIDENCE FOR PARTIAL ALLOSTERIC AGONISM IN COMPARISON WITH CXCL12 CHEMOKINE. J Biol Chem 291:15881-95
Pantouris, Georgios; Syed, Mansoor Ali; Fan, Chengpeng et al. (2015) An Analysis of MIF Structural Features that Control Functional Activation of CD74. Chem Biol 22:1197-205
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
Rajasekaran, Deepa; Zierow, Swen; Syed, Mansoor et al. (2014) Targeting distinct tautomerase sites of D-DT and MIF with a single molecule for inhibition of neutrophil lung recruitment. FASEB J 28:4961-71
Ioannou, Kyriaki; Cheng, Kai Fan; Crichlow, Gregg V et al. (2014) ISO-66, a novel inhibitor of macrophage migration, shows efficacy in melanoma and colon cancer models. Int J Oncol 45:1457-68
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
Crichlow, Gregg V; Fan, Chengpeng; Keeler, Camille et al. (2012) Structural interactions dictate the kinetics of macrophage migration inhibitory factor inhibition by different cancer-preventive isothiocyanates. Biochemistry 51:7506-14

Showing the most recent 10 out of 22 publications