SF3B1 is a stress-sensitive splicing factor that regulates both HSF1 concentration and activity

• Published in: PloS one 2017-04, Vol.12 (4), p.e0176382-e0176382
• Main Authors: Kim Guisbert, Karen S, Guisbert, Eric
• Format: Article
• Language: English
• Subjects: Alternative splicing; Biology and Life Sciences; Caenorhabditis elegans; Cancer; Crosstalk; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drosophila; Epoxy Compounds - pharmacology; Experiments; Gene expression; Genetic aspects; Genetic screening; Health aspects; Heat; Heat shock; Heat shock factors; Heat shock proteins; Heat Shock Transcription Factors; Heat-Shock Response - drug effects; Heat-Shock Response - genetics; HeLa Cells; Humans; Inhibition; Insects; Leukemia; Macrolides - pharmacology; Mutation; Phosphoproteins - antagonists & inhibitors; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Protein folding; RNA Interference; RNA Splicing; RNA Splicing Factors - antagonists & inhibitors; RNA Splicing Factors - genetics; RNA Splicing Factors - metabolism; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; Splicing factors; Stress; Stresses; Temperature; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0176382

The heat shock response (HSR) is a well-conserved, cytoprotective stress response that activates the HSF1 transcription factor. During severe stress, cells inhibit mRNA splicing which also serves a cytoprotective function via inhibition of gene expression. Despite their functional interconnectedness, there have not been any previous reports of crosstalk between these two pathways. In a genetic screen, we identified SF3B1, a core component of the U2 snRNP subunit of the spliceosome, as a regulator of the heat shock response in Caenorhabditis elegans. Here, we show that this regulatory connection is conserved in cultured human cells and that there are at least two distinct pathways by which SF3B1 can regulate the HSR. First, inhibition of SF3B1 with moderate levels of Pladienolide B, a previously established small molecule inhibitor of SF3B1, affects the transcriptional activation of HSF1, the transcription factor that mediates the HSR. However, both higher levels of Pladienolide B and SF3B1 siRNA knockdown also change the concentration of HSF1, a form of HSR regulation that has not been previously documented during normal physiology but is observed in some forms of cancer. Intriguingly, mutations in SF3B1 have also been associated with several distinct types of cancer. Finally, we show that regulation of alternative splicing by SF3B1 is sensitive to temperature, providing a new mechanism by which temperature stress can remodel the transcriptome.