title: 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 complex.
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.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore, 21201, USA.
authors.forename: Andrei E
authors.initials: AE
authors.lastname: Medvedev
authors.forename: Karen
authors.initials: K
authors.lastname: Thomas
authors.forename: Agnes
authors.initials: A
authors.lastname: Awomoyi
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kuhns
authors.forename: John I
authors.initials: JI
authors.lastname: Gallin
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation / Q000378:metabolism; D001424:Bacterial Infections / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D002460:Cell Line; D003593:Cytoplasm / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D053594:Myeloid Differentiation Factor 88; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D012008:Recurrence; D017384:Sequence Deletion / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D007375:Interleukin-1; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases