Isoginkgetin leads to decreased protein synthesis and activates an ATF4-dependent transcriptional response

Isoginkgetin (IGG) is a small molecule inhibitor of pre-mRNA splicing. Failure to accurately remove introns could lead to the production of aberrant mRNAs and proteins. The cellular responses to splicing stress are not well defined. Here, we used oligonucleotide microarrays to assess genome wide changes in gene expression associated with exposure to IGG. Two of the 3 enriched pathways identified using PANTHER analysis of differentially expressed transcripts are linked to the ATF4 transcription factor. We confirmed that ATF4 was selectively translated and upregulated in response IGG despite an almost complete block to total protein synthesis. Importantly, partial disruption of the ATF4 gene using CRISPR-mediated gene editing prevented IGG-induced changes in gene expression. Remarkably, another spliceosome inhibitor, pladienolide B, did not inhibit translation, activate ATF4 or increase ATF4-dependent gene expression. Taken together, IGG activates ATF4 and an ATF4-dependent transcriptional response but these effects are not common to all spliceosome inhibitors.