The IRAK-M death domain: a tale of three surfaces

Berke Gürkan, Hessel Poelman, Liza Pereverzeva, Danielle Kruijswijk, Alex F. de Vos, Anouk G. Groenen, Edgar E. Nollet, Kanin Wichapong, Esther Lutgens, Tom van der Poll, Jiangfeng Du, W. Joost Wiersinga, Gerry A.F. Nicolaes, Cornelis van ‘t Veer

Research output: Contribution to journalArticlepeer-review

Abstract

The anti-inflammatory interleukin-1 receptor associated kinase-M (IRAK-M) is a negative regulator of MyD88/IRAK-4/IRAK-1 signaling. However, IRAK-M has also been reported to activate NF-κB through the MyD88/IRAK-4/IRAK-M myddosome in a MEKK-3 dependent manner. Here we provide support that IRAK-M uses three surfaces of its Death Domain (DD) to activate NF-κB downstream of MyD88/IRAK-4/IRAK-M. Surface 1, with central residue Trp74, binds to MyD88/IRAK-4. Surface 2, with central Lys60, associates with other IRAK-M DDs to form an IRAK-M homotetramer under the MyD88/IRAK-4 scaffold. Surface 3; with central residue Arg97 is located on the opposite side of Trp74 in the IRAK-M DD tetramer, lacks any interaction points with the MyD88/IRAK-4 complex. Although the IRAK-M DD residue Arg97 is not directly involved in the association with MyD88/IRAK-4, Arg97 was responsible for 50% of the NF-κB activation though the MyD88/IRAK-4/IRAK-M myddosome. Arg97 was also found to be pivotal for IRAK-M’s interaction with IRAK-1, and important for IRAK-M’s interaction with TRAF6. Residue Arg97 was responsible for 50% of the NF-κB generated by MyD88/IRAK-4/IRAK-M myddosome in IRAK-1/MEKK3 double knockout cells. By structural modeling we found that the IRAK-M tetramer surface around Arg97 has excellent properties that allow formation of an IRAK-M homo-octamer. This model explains why mutation of Arg97 results in an IRAK-M molecule with increased inhibitory properties: it still binds to myddosome, competing with myddosome IRAK-1 binding, while resulting in less NF-κB formation. The findings further identify the structure-function properties of IRAK-M, which is a potential therapeutic target in inflammatory disease.

Original languageEnglish (US)
Article number1265455
JournalFrontiers in Molecular Biosciences
Volume10
DOIs
StatePublished - 2023

Keywords

  • IRAK-3
  • IRAK-M
  • Toll-like receptors
  • death domain
  • inflammation
  • myddosome

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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