Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock

Abstract

The cellular response to stresses such as heat shock involves changes in gene expression¹. It is well known that the splicing of messenger RNA precursors is generally repressed on heat shock^2,3, but the factors responsible have not been identified^4,5,6,7,8. SRp38 is an SR protein splicing factor^9,10 that functions as a general repressor of splicing. It is activated by dephosphorylation and required for splicing repression in M-phase cells¹¹. Here we show that SRp38 is also dephosphorylated on heat shock and that this dephosphorylation correlates with splicing inhibition. Notably, depletion of SRp38 from heat-shocked cell extracts derepresses splicing, and adding back dephosphorylated SRp38 specifically restores inhibition. We further show that dephosphorylated SRp38 interacts with a U1 small nuclear ribonucleoprotein particle (snRNP) protein, and that this interaction interferes with 5′-splice-site recognition by the U1 snRNP. Finally, SRp38-deficient DT40 cells show an altered cell-cycle profile consistent with a mitotic defect; they are also temperature sensitive and defective in recovery after heat shock. SRp38 thus plays a crucial role in cell survival under stress conditions by inhibiting the splicing machinery.