Dimethyl Fumarate Disrupts Human Innate Immune Signaling by Targeting the IRAK4-MyD88 Complex

J Immunol. 2019 May 1;202(9):2737-2746. doi: 10.4049/jimmunol.1801627. Epub 2019 Mar 18.


Dimethyl fumarate (DMF) is a prescribed treatment for multiple sclerosis and has also been used to treat psoriasis. The electrophilicity of DMF suggests that its immunosuppressive activity is related to the covalent modification of cysteine residues in the human proteome. Nonetheless, our understanding of the proteins modified by DMF in human immune cells and the functional consequences of these reactions remains incomplete. In this study, we report that DMF inhibits human plasmacytoid dendritic cell function through a mechanism of action that is independent of the major electrophile sensor NRF2. Using chemical proteomics, we instead identify cysteine 13 of the innate immune kinase IRAK4 as a principal cellular target of DMF. We show that DMF blocks IRAK4-MyD88 interactions and IRAK4-mediated cytokine production in a cysteine 13-dependent manner. Our studies thus identify a proteomic hotspot for DMF action that constitutes a druggable protein-protein interface crucial for initiating innate immune responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Cytokines / immunology
  • Dendritic Cells / immunology*
  • Dimethyl Fumarate / pharmacology*
  • Female
  • Humans
  • Immunity, Innate / drug effects*
  • Interleukin-1 Receptor-Associated Kinases / immunology*
  • Middle Aged
  • Multiprotein Complexes / immunology*
  • Myeloid Differentiation Factor 88 / immunology*
  • Plasma Cells / immunology*
  • Signal Transduction / drug effects*


  • Cytokines
  • MYD88 protein, human
  • Multiprotein Complexes
  • Myeloid Differentiation Factor 88
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • Dimethyl Fumarate