The mechanism of activation of IRAK1 and IRAK4 by interleukin-1 and Toll-like receptor agonists

The Biochemical Journal
Stefan VollmerPhilip Cohen

Abstract

We have developed the first assays that measure the protein kinase activities of interleukin-1 receptor-associated kinase 1 (IRAK1) and IRAK4 reliably in human cell extracts, by employing Pellino1 as a substrate in conjunction with specific pharmacological inhibitors of IRAK1 and IRAK4. We exploited these assays to show that IRAK4 was constitutively active and that its intrinsic activity towards Pellino1 was not increased significantly by stimulation with interleukin-1 (IL-1) in IL-1R-expressing HEK293 cells, Pam3CSK4-stimulated human THP1 monocytes or primary human macrophages. Our results, in conjunction with those of other investigators, suggest that the IL-1-stimulated trans-autophosphorylation of IRAK4 is initiated by the myeloid differentiation primary response gene 88-induced dimerization of IRAK4 and is not caused by an increase in the intrinsic catalytic activity of IRAK4. In contrast with IRAK4, we found that IRAK1 was inactive in unstimulated cells and converted into an active protein kinase in response to IL-1 or Pam3CSK4 in human cells. Surprisingly, the IL-1-stimulated activation of IRAK1 was not affected by pharmacological inhibition of IRAK4 and not reversed by dephosphorylation and/or deubiquitylation, suggesti...Continue Reading

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Citations

Dec 17, 2017·Immunological Reviews·Diana BoraschiMichael U Martin
Dec 7, 2017·Proceedings of the National Academy of Sciences of the United States of America·Li WangHao Wu
Sep 27, 2018·Journal of Leukocyte Biology·Katherine R Balka, Dominic De Nardo
Oct 3, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Anil K SinghSalahuddin Ahmed
Jul 22, 2018·The EMBO Journal·Matous HrdinkaMads Gyrd-Hansen
May 2, 2019·Science Signaling·Mialy M DeFeliceSergi Regot
Apr 3, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Viral G JainLouis J Muglia
May 20, 2020·The Journal of Clinical Investigation·Mabruka AlfaidiA Wayne Orr
Feb 11, 2020·Frontiers in Behavioral Neuroscience·Jason G ThomeMatthew J Robson
Mar 28, 2019·Expert Opinion on Therapeutic Patents·William T McElroy
Mar 15, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Anna A KiselevaErica A Golemis
May 23, 2020·Brain, Behavior, and Immunity·Katrien PletinckxTorsten R Dunkern
Jan 26, 2021·ACS Medicinal Chemistry Letters·Yun ChenWenhu Duan
Apr 1, 2019·Journal of Innate Immunity·Azzeddine DakhamaHong Wei Chu
Nov 8, 2021·Current Opinion in Hematology·Joshua Bennett, Daniel T Starczynowski

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Methods Mentioned

BETA
density gradient centrifugation
immunoprecipitation
transfection

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