title: IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal).
abstract: Signal transduction by Toll-like receptor 2 (TLR2) and TLR4 requires the adaptors MyD88 and Mal (MyD88 adaptor-like) and serine/threonine kinases, interleukin-1 receptor-associated kinases IRAK1 and IRAK4. We have found that both IRAK1 and IRAK4 can directly phosphorylate Mal. In addition, co-expression of Mal with either IRAK resulted in depletion of Mal from cell lysates. This is likely to be due to Mal phosphorylation by the IRAKs because kinase-inactive forms of either IRAK had no effect. Furthermore, lipopolysaccharide stimulation resulted in ubiquitination and degradation of Mal, which was inhibited using an IRAK1/4 inhibitor or by knocking down expression of IRAK1 and IRAK4. MyD88 is not a substrate for either IRAK and did not undergo degradation. We therefore conclude that Mal is a substrate for IRAK1 and IRAK4 with phosphorylation promoting ubiquitination and degradation of Mal. This process may serve to negatively regulate signaling by TLR2 and TLR4.
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland. aidunne@tcd.ie
authors.forename: Aisling
authors.initials: A
authors.lastname: Dunne
authors.forename: Susan
authors.initials: S
authors.lastname: Carpenter
authors.forename: Constantinos
authors.initials: C
authors.lastname: Brikos
authors.forename: Pearl
authors.initials: P
authors.lastname: Gray
authors.forename: Astrid
authors.initials: A
authors.lastname: Strelow
authors.forename: Holger
authors.initials: H
authors.lastname: Wesche
authors.forename: Nick
authors.initials: N
authors.lastname: Morrice
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
mesh_terms: D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000737:chemistry; D013058:Mass Spectrometry / Q000379:methods; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008954:Models, Biological; D009185:Myelin Proteins / Q000378:metabolism*; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D010766:Phosphorylation; D011510:Proteolipids / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry
chemical_list: D008070:Lipopolysaccharides; C569026:MAL protein, human; C507779:MYD88 protein, human; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88; D011510:Proteolipids; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D025801:Ubiquitin; C507768:IRAK1 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
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