# Immediate early splicing controls translation in activated T-cells and is mediated by hnRNPC2 phosphorylation

## TL;DR

T-cell activation triggers a rapid splicing switch that reduces protein translation, helping coordinate gene expression changes.

## Contribution

The discovery that T-cell activation induces immediate early splicing (IES) via hnRNPC2 phosphorylation, which reduces translation.

## Key findings

- Immediate early splicing (IES) is mediated by phosphorylation of hnRNPC2 and requires MEK/ERK and PKCθ activity.
- IES affects mRNAs encoding translation components like eIF5A, reducing de novo protein synthesis after T-cell activation.
- IES occurs independently of new protein synthesis and helps coordinate gene expression during T-cell activation.

## Abstract

The fast and transient induction of immediate early genes orchestrates the cellular response to various stimuli. These stimuli trigger phosphorylation cascades that promote immediate early gene transcription independent of de novo protein synthesis. Here we show that the same phosphorylation cascades also target the splicing machinery, inducing an analogous splicing switch that we call immediate early splicing (IES). We characterize hnRNPC2-controlled IES, which depends on the MEK-ERK pathway and the T cell-specific kinase PKCθ. This splicing switch mainly targets components of the translation machinery, such as mRNAs encoding ribosomal proteins and eIF5A. Inducing the eIF5A IES protein variant is by itself sufficient to reduce global translation, and consistently, we observe reduced de novo protein synthesis early after T cell activation. We suggest that immediate early splicing and the ensuing transient decrease in translation efficiency help to coordinate the extensive changes in gene expression during T cell activation. Together, these findings set a paradigm for fast and transient alternative splicing in the immediate cellular response to activation, and provide evidence for its functional relevance during T-cell stimulation.

Activation signals cause immediate early genes to be transcribed rapidly and independently of de novo translation. Here, T cell activation is found to also involve a fast and transient splicing switch.

Immediate early splicing (IES) upon T-cell activation is independent of de novo translation upon cellular activation/stimulation.IES in T cells is controlled through phosphorylation of hnRNPC2 and requires MEK/ERK and PKCθ activity.IES in T cells affects many components of the translation machinery such as eIF5A.IES thereby reduces de novo translation in the hours directly after T cell activation.

Immediate early splicing (IES) upon T-cell activation is independent of de novo translation upon cellular activation/stimulation.

IES in T cells is controlled through phosphorylation of hnRNPC2 and requires MEK/ERK and PKCθ activity.

IES in T cells affects many components of the translation machinery such as eIF5A.

IES thereby reduces de novo translation in the hours directly after T cell activation.

Immediate early splicing represents a fast and transient splicing switch independent of de novo translation upon cellular stimulation.