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The Journal of Immunology, 2005, 174: 6587-6591.
Copyright © 2005 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Expression of IL-1 Receptor-Associated Kinase-4 (IRAK-4) Proteins with Mutations Identified in a Patient with Recurrent Bacterial Infections Alters Normal IRAK-4 Interaction with Components of the IL-1 Receptor Complex1

Andrei E. Medvedev*, Karen Thomas*, Agnes Awomoyi*, Douglas B. Kuhns{dagger}, John I. Gallin{ddagger}, Xiaoxia Li§ and Stefanie N. Vogel2,*

* Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201; {dagger} Clinical Services Program, Science Applications International Corporation-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702; {ddagger} Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and § Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195

In a patient with recurrent bacterial infections and profound hyporesponsiveness to LPS and IL-1, we previously identified two mutations in IL-1R-associated kinase-4 (IRAK-4) that encoded proteins with truncated kinase domains. Overexpression of either of these mutant IRAK-4 variants in HEK293 cells failed to activate endogenous IRAK-1 and suppressed IL-1-induced IRAK-1 kinase activity, in contrast to wild-type (WT) IRAK-4. In this study, interactions of WT and mutant IRAK-4 species with IL-1R, IRAK-1, and MyD88 in HEK293 transfectants were compared. IL-1 induced a strong interaction among the IL-1R, activated IRAK-1, MyD88, and WT, but not mutant, IRAK-4. Truncated IRAK-4 proteins constitutively interacted more strongly with MyD88 and blunted IL-1-induced recruitment of IRAK-1 and MyD88 to the IL-1R. Thus, decreased IL-1-induced association of IRAK-1 and MyD88 with the IL-1RI may result from sequestration of cytoplasmic MyD88 by IRAK-4 mutant proteins. Therefore, mimetics of these truncated IRAK-4 proteins may represent a novel approach to mitigating hyperinflammatory states.




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