Chemical proteomic map of dimethyl fumarate–sensitive cysteines in primary human T cells
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Chemical proteomics analysis suggests the mechanism of action of a drug used to treat autoimmune diseases.
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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 [184]
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 [184]
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 [184]
Disrupting the PKCθ-CD28 interaction reduced T cell activation.
“Disrupting the interaction of PKCθ with the costimulatory receptor CD28 reduced T cell activation”
From Advances in covalent drug discovery (2022) · cites this paper as [184]
Fumarate inhibits a variety of α-KGDDs.
“As mentioned, fumarate also inhibits a variety of α-KGDDs, enzymes involved in multiple cellular processes, from metabolism to signalling and epigenetics90-92”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [90]
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References 71 · Cited by 194
Research works printed but not linked: 2
- [46]Weerapana E Speers AE Cravatt BF Tandem orthogonal proteolysis-activity-based protein profiling (TOP-ABPP)--a general method for mapping sites of probe modification in proteomes Nature protocols 2 1414 1425 2007 17545978
- [60]Zhang EY Kong KF Altman A The yin and yang of protein kinase C-theta (PKCtheta): a novel drug target for selective immunosuppression Advances in pharmacology 66 267 312 2013 23433459 PMC3903317
- Authors
- Blewett, M. M., Xie, J., Zaro, B. W., Backus, K. M., Altman, A., Teijaro, J. R., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
- La Jolla Institute for Immunology (US)
- Corresponding author
- Teijaro, John R.
- Cravatt, Benjamin F.
- Venue
- Science Signaling
- Published
- 2016-09-13
- Volume
- 9
- Issue
- 445
- Pages
- rs10-rs10
- ISSN
- 1937-9145 (ISSN-L)
- 1945-0877
- PMC
- PMC5068918
- OpenAlex
- W2519889757
- Cited by
- 194
- References
- 71
- Citations by year
- 2026: 17 · 2025: 18 · 2024: 16 · 2023: 11 · 2022: 21 · 2021: 30 · 2020: 19 · 2019: 20 · 2018: 29 · 2017: 11 · 2016: 2
- FWCI
- 9.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Signaling (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (CA087660, GM108208)
- Donald E. and Delia B. Baxter Foundation Faculty Scholar Program
- LEO Pharma
- NSF Graduate Research Fellowship Program (DGE-1346837)
- Hertz Foundation
- American Cancer Society (PF-15-142-01_CDD)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- dimethyl fumarate, monomethyl fumarate, T cell activation, protein kinase C, CD28, C2 domain, CXXC motif, covalent protein modification, autoimmune disease therapy
- MeSH terms
- Dimethyl Fumarate, Animals, Cysteine, Humans, Lymphocyte Activation, Protein Kinase C, T-Lymphocytes, CD28 Antigens, Mice, Knockout, Proteome, Proteomics, Mice
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