Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adaptor Proteins, Signal Transducing
-
Antigens, Differentiation / metabolism
-
Bacterial Infections / enzymology
-
Bacterial Infections / genetics*
-
Bacterial Infections / immunology*
-
Cell Line
-
Cytoplasm / enzymology
-
Cytoplasm / genetics
-
Cytoplasm / immunology
-
Female
-
Humans
-
Interleukin-1 / antagonists & inhibitors
-
Interleukin-1 / pharmacology
-
Interleukin-1 Receptor-Associated Kinases
-
Lipopolysaccharides / administration & dosage
-
Lipopolysaccharides / antagonists & inhibitors
-
Myeloid Differentiation Factor 88
-
Phosphotransferases (Alcohol Group Acceptor) / biosynthesis*
-
Phosphotransferases (Alcohol Group Acceptor) / genetics*
-
Phosphotransferases (Alcohol Group Acceptor) / metabolism
-
Phosphotransferases (Alcohol Group Acceptor) / physiology
-
Protein Transport / genetics
-
Protein Transport / immunology
-
Receptors, Immunologic / metabolism
-
Receptors, Interleukin-1 / metabolism*
-
Recurrence
-
Sequence Deletion / immunology*
-
Signal Transduction / genetics
-
Signal Transduction / immunology
Substances
-
Adaptor Proteins, Signal Transducing
-
Antigens, Differentiation
-
Interleukin-1
-
Lipopolysaccharides
-
MYD88 protein, human
-
Myeloid Differentiation Factor 88
-
Receptors, Immunologic
-
Receptors, Interleukin-1
-
Phosphotransferases (Alcohol Group Acceptor)
-
Interleukin-1 Receptor-Associated Kinases