IRAK1 and IRAK4 Promote Phosphorylation,Ubiquitination, and Degradation of MyD88 Adaptor-like (Mal) |
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| Authors: | Aisling Dunne Susan Carpenter Constantinos Brikos Pearl Gray Astrid Strelow Holger Wesche Nick Morrice Luke A J O'Neill |
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| Institution: | From the ‡School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland, ;¶Amgen San Francisco, South San Francisco, California 94080, ;§CFD Therapeutics, San Francisco, California 94080, and ;the ‖Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom |
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| 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. |
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| Keywords: | Death Domain Interleukin Receptor-associated Kinase (IRAK) Mal TIRAP Phosphorylation Enzymes Ubiquitination |
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