Proteomics

Dataset Information

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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.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, T Cell

SUBMITTER: Ekaterina Vinogradova  

LAB HEAD: Ekaterina Viktorovna Vinogradova

PROVIDER: PXD056704 | Pride | 2024-10-21

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
01132023_EV1_147d1_10plex_01.raw Raw
01132023_EV1_147d2_10plex_01.raw Raw
01192023_EV1_151_10pl_noRTS_01.raw Raw
01192023_EV1_151_10pl_noRTS_02.raw Raw
01192023_EV1_151_10pl_noRTS_03.raw Raw
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Publications


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 chemical probe 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  ...[more]

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