Human Prefoldin Modulates Co-transcriptional Pre-mRNA Splicing

Prefoldin is a heterohexameric complex conserved from archaea to humans that plays a cochaperone role during the cotranslational folding of actin and tubulin monomers. Additional functions of prefoldin in the cell nucleus have been described, including a positive contribution to transcription elongation and chromatin dynamics in yeast. Here we show that prefoldin depletion provoked transcriptional alterations across the genome of human cells. Severe pre-mRNA splicing defects were also detected, particularly under serum stimulation conditions. We found a significant impairment of co-transcriptional splicing during transcription elongation, that explains why the expression of long genes with a high number of introns was affected the most. We detected prefoldin binding to the gene body of transcribed genes and found that its lack caused significant decrease in the levels of Ser2 phosphorylation of the RNA polymerase II carboxiterminal domain. Moreover, lack of prefoldin reduced the association of splicing factor U2AF65 with chromatin, an association that is known to be dependent on Ser2 phosphorylation. Considered altogether the reported results indicate that human prefoldin is able to modulate gene expression by influencing phosphorylation of elongating RNA polymerase II, and thereby regulating co-transcriptional splicing efficiency.