Research ResourceImmunology

Chemical proteomic map of dimethyl fumarate–sensitive cysteines in primary human T cells

Sci. Signal.  13 Sep 2016:
Vol. 9, Issue 445, pp. rs10
DOI: 10.1126/scisignal.aaf7694

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Uncovering how a drug works

The drug dimethyl fumarate (DMF), which is used to treat autoimmune diseases, including psoriasis and multiple sclerosis, may act by modifying cysteine residues in proteins. A better understanding of its mechanism of action and target proteins is required because it can cause life-threatening infections in some patients. Blewett et al. used a chemical proteomics approach to identify cysteine residues in human T cell proteins that reacted with DMF. One such target, the kinase PKCθ, contains two cysteine residues that were targeted by DMF, which prevented PKCθ from interacting with the T cell costimulatory receptor CD28 and mediating full T cell activation. This approach should aid in developing similar drugs with fewer side effects.

Abstract

Dimethyl fumarate (DMF) is an electrophilic drug that is used to treat autoimmune conditions, including multiple sclerosis and psoriasis. The mechanism of action of DMF is unclear but may involve the covalent modification of proteins or DMF serving as a prodrug that is converted to monomethyl fumarate (MMF). We found that DMF, but not MMF, blocked the activation of primary human and mouse T cells. Using a quantitative, site-specific chemical proteomic platform, we determined the DMF sensitivity of >2400 cysteine residues in human T cells. Cysteines sensitive to DMF, but not MMF, were identified in several proteins with established biochemical or genetic links to T cell function, including protein kinase Cθ (PKCθ). DMF blocked the association of PKCθ with the costimulatory receptor CD28 by perturbing a CXXC motif in the C2 domain of this kinase. Mutation of these DMF-sensitive cysteines also impaired PKCθ-CD28 interactions and T cell activation, designating the C2 domain of PKCθ as a key functional, electrophile-sensing module important for T cell biology.

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