Dimethyl Fumarate Disrupts Human Innate Immune Signaling by Targeting the IRAK4–MyD88 Complex
Open accessAbstract
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.
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Disrupting the IRAK4-MYD88 interaction suppressed interferon-α production in plasmacytoid dendritic cells.
“disrupting the IRAK4–MYD88 interaction suppressed the production of interferon-α in plasmacytoid dendritic cells184,185.”
From Advances in covalent drug discovery (2022) · cites this paper as [185]
In both cases, covalent engagement of a cysteine residue disrupted a protein-protein interaction to modulate immune cell function.
“In both cases, covalent engagement of a cysteine residue disrupted a protein–protein interaction to modulate immune cell function.”
From Advances in covalent drug discovery (2022) · cites this paper as [185]
The direct covalent targets of dimethyl fumarate remained unclear until recently, despite its long use for psoriasis and FDA approval for multiple sclerosis in 2013.
“Although dimethyl fumarate has been used for three decades to treat psoriasis and was approved by the FDA in 2013 for the treatment of multiple sclerosis, the direct covalent targets of dimethyl fumarate remained unclear until more recently.”
From Advances in covalent drug discovery (2022) · cites this paper as [185]
Separate chemoproteomic studies identified PKCθ and IRAK4 as targets of dimethyl fumarate.
“In separate studies, chemoproteomic approaches were used to identify protein kinase Cθ (PKCθ) and IRAK4 as targets of dimethyl fumarate184,185.”
From Advances in covalent drug discovery (2022) · cites this paper as [185]
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- Authors
- Zaro, B. W., Vinogradova, E. V., Lazar, D. C., Blewett, M. M., Suciu, R. M., Takaya, J., Studer, S., de la Torre, J. C., Casanova, J.-L., Cravatt, B. F., & Teijaro, J. R.
- Affiliations
- Scripps Research Institute (US)
- Department of Immunology and Infectious Disease, The Scripps Research Institute , La Jolla, CA 92037
- Rockefeller University (US)
- Corresponding author
- Takaya, Junichiro
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-05-01
- Volume
- 202
- Issue
- 9
- Pages
- 2737-2746
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC6478521
- OpenAlex
- W2921222882
- Cited by
- 68
- References
- 61
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 11 · 2023: 5 · 2022: 11 · 2021: 12 · 2020: 9 · 2019: 5
- FWCI
- 3.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (1346837)
- American Cancer Society (PF-15-142-01-CDD)
- Donald E. and Delia B. Baxter Foundation
- Life Sciences Research Foundation
- National Institutes of Health
- National Cancer Institute (R35CA231991)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- dimethyl fumarate, IRAK4, MyD88, plasmacytoid dendritic cells, innate immune signaling, protein-protein interaction inhibition, cytokine production, immunosuppression, chemoproteomics, multiple sclerosis treatment
- MeSH terms
- Dimethyl Fumarate, Adult, Dendritic Cells, Female, Humans, Immunity, Innate, Middle Aged, Plasma Cells, Signal Transduction, Cytokines, Multiprotein Complexes, Interleukin-1 Receptor-Associated Kinases, Myeloid Differentiation Factor 88
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