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Covalent targeting of splicing in T cells
Kevin A Scott1, Hiroyuki Kojima1, Nathalie Ropek1
1Department of Chemical Immunology and Proteomics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Cell Chemical Biology
|November 26, 2024
Summary
Researchers developed chemical probes targeting splicing factor SF3B1, leading to selective T-cell loss of ITK. This work highlights immune state-dependent protein expression changes and potential for covalent targeting of splicing factors.
Area of Science:
- Biochemistry
- Immunology
- Molecular Biology
Background:
- Therapeutic targeting of RNA splicing is of significant interest, but chemical probes for splicing proteins are limited.
- Interleukin 2-inducible T-cell kinase (ITK) plays a crucial role in T-cell signaling.
Purpose of the Study:
- To develop chemical probes for targeting splicing factors.
- To investigate the mechanism of state-dependent protein loss in T-cells.
- To explore the potential of covalent chemistry for targeting splicing factors.
Main Methods:
- Synthesis and application of stereoisomeric acrylamide EV96 and analogues.
- Mechanistic investigations involving protein turnover rates and alternative splicing analysis.
- Activity-based protein profiling (ABPP) using electrophilic scout fragments.
Main Results:
- EV96 selectively induced T-cell state-dependent loss of ITK by targeting SF3B1.
- State-dependency was linked to differential protein turnover and ITK mRNA alternative splicing.
- Demonstrated covalent ligandability of numerous splicing factors and regulators in T-cells.
Conclusions:
- Chemical perturbation of splicing can induce immune state-dependent changes in protein expression.
- Covalent targeting of splicing factors presents a promising therapeutic strategy.
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