Covalent targeting of splicing in T cells Journal Article
| Authors: | Scott, K. A.; Kojima, H.; Ropek, N.; Warren, C. D.; Zhang, T. L.; Hogg, S. J.; Sanford, H.; Webster, C.; Zhang, X.; Rahman, J.; Melillo, B.; Cravatt, B. F.; Lyu, J.; Abdel-Wahab, O.; Vinogradova, E. V. |
| Article Title: | Covalent targeting of splicing in T cells |
| Abstract: | Despite significant interest in therapeutic targeting of splicing, few chemical probes are available for the proteins involved in splicing. Here, we show that elaborated stereoisomeric acrylamide EV96 and its analogues lead to a selective T cell state-dependent loss of interleukin 2-inducible T cell kinase (ITK) by targeting one of the core splicing factors SF3B1. Mechanistic investigations suggest that the state-dependency stems from a combination of differential protein turnover rates and extensive ITK mRNA alternative splicing. We further introduce the most comprehensive list to date of proteins involved in splicing and leverage cysteine- and protein-directed activity-based protein profiling with electrophilic scout fragments to demonstrate covalent ligandability for many classes of splicing factors and splicing regulators in T cells. Taken together, our findings show how chemical perturbation of splicing can lead to immune state-dependent changes in protein expression and provide evidence for the broad potential to target splicing factors with covalent chemistry. © 2024 |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; t lymphocyte; t-lymphocytes; metabolism; enzyme inhibition; protein metabolism; cytotoxicity; drug effect; enzyme inhibitor; protein tyrosine kinase; cytokine; chemistry; alternative splicing; alternative rna splicing; chemical structure; molecular structure; protein-tyrosine kinases; spliceosome; t lymphocyte activation; immunopathology; rna splicing; covalent bond; peptides and proteins; humans; human; article; acrylamide derivative; acrylamide; emt protein-tyrosine kinase; rna splicing factor; rna splicing factors; protein fingerprinting; activity-based protein profiling; splicing factor 3b subunit 1; covalent immunomodulators; interleukin-2-inducible t-cell kinase; ev96; interleukin 2 inducible t cell kinase; protein sf3b1; electrophilicity |
| Journal Title: | Cell Chemical Biology |
| Volume: | 32 |
| Issue: | 1 |
| ISSN: | 2451-9456 |
| Publisher: | Cell Press |
| Date Published: | 2025-01-16 |
| Start Page: | 201 |
| End Page: | 218.e17 |
| Language: | English |
| DOI: | 10.1016/j.chembiol.2024.10.010 |
| PUBMED: | 39591969 |
| PROVIDER: | scopus |
| PMCID: | PMC12068509 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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