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Abstract
This Podcast features an interview with Benjamin Cravatt, John Teijaro, and Megan Blewett authors of a Research Resource that appears in the 13 September 2016 issue of Science Signaling, about the proteins in human immune cells that are modified by the drug dimethyl fumarate (DMF). DMF is used to treat the autoimmune diseases psoriasis and multiple sclerosis, but the molecular basis of its immunosuppressive properties is not well understood. This drug can covalently modify cysteine residues in proteins, but it is also converted in vivo to monomethyl fumarate (MMF), which can activate signaling through G protein–coupled receptors. Blewett et al. found that DMF, but not MMF, inhibited the activation of primary human T cells in vitro. Using a quantitative chemical proteomics approach, the authors identified human T cell proteins that contained cysteines that were modified by DMF, but not MMF. One of the proteins they identified was protein kinase C θ (PKCθ), which plays a role in T cell activation. Modification of PKCθ by DMF prevented PKCθ from interacting with the costimulatory receptor CD28, thus reducing T cell activation. A better understanding of the biochemistry of DMF may enable the development of drugs that deliver the therapeutic benefits of DMF without the side effects.
