Cell Biology PIP-Influenced Transcription

Annalisa M. VanHook

Science Signaling, AAAS, Washington, DC 20005, USA

Cell signaling often results in changes in gene expression, which can occur through the regulated nucleocytoplasmic shuttling of transcription factors. Han and Emr report that lipid binding regulates the shuttling and activity of a transcriptional regulator in yeast. Phosphatidylinositol phosphates (PIPs) are lipids that mediate signaling in various organisms, and PI(3,5)P₂ is a lipid produced at endosomal membranes in yeast. The authors identified the transcriptional regulator Tup1 as a PI(3,5)P₂-binding protein. Tup1 participates in both repressor and activator complexes that regulate the transcriptional status of some of the GAL genes, which encode proteins required for metabolizing galactose (Gal). As a repressor, Tup1 forms a complex with Cyc8 that recruits chromatin-modifying proteins and promotes nucleosome formation; as an activator, the Cyc8-Tup1 complex cooperates with Cti6 to recruit transcriptional coactivator complexes. The yeast strain SEY6210 cannot activate GAL1 through the dominant Gal4 pathway but is nevertheless able to activate GAL1 to grow on medium containing Gal as the only carbon source. However, mutants that also could not synthesize the PI(3,5)P₂ precursor PI(3)P were unable to grow on Gal medium, indicating that a PI(3,5)P₂-dependent pathway was able to activate GAL1 in parallel to Gal4. Whereas GAL1 was induced upon shifting SEY6210 cells from glucose-containing medium into medium in which Gal was the only source of carbon, it was not induced in fab1 mutants, which lack the endosomally localized enzyme that catalyzes the conversion of PI(3)P to PI(3,5)P₂. Gal shifting wild-type (WT) cells caused a decrease in nuclear-localized Tup1 with a corresponding increase in the amount of Tup1 present in the cytoplasm and at vacuolar endosomal membranes, but no Tup1 was present at vacuoles of fab1 cells either before or after Gal shifting. Although Cti6 was present mainly in the nuclei of WT cells both before and after Gal shifting, Cti6 accumulated in the cytoplasm of fab1 cells after Gal shift. Furthermore, Cti6 also bound PI(3,5)P₂ in vitro, and mutant forms of Cti6 unable to bind to PIP accumulated in the cytoplasm of WT cells upon Gal shift. PI(3,5)P₂ was also required for the Cti6-dependent recruitment of transcriptional coactivator complexes to the GAL1 promoter. These results suggest a model in which PI(3,5)P₂ mediates recruitment of Tup1 and Cti6 to the late endosome for assembly of the Cti6-Cyc8-Tup1 complex, which is required for switching Tup1 from a transcriptional corepressor to a coactivator. The possibility that lipid binding may directly modulate the activities of transcriptional regulators in other contexts and species is intriguing, and whether this is a widespread mechanism for transducing signals from the cytoplasm to the nucleus remains to be seen.

B.-K. Han, S. D. Emr, Phosphoinositide [PI(3,5)P₂] lipid-dependent regulation of the general transcriptional regulator Tup1. Genes Dev. 25, 984–995 (2011). [Abstract] [Full Text]

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