Glc7/PP1 dephosphorylates histone H3T11 to regulate autophagy and telomere silencing in response to nutrient availability

How cells adapt their gene expression to nutritional changes remains poorly understood. Histone H3T11 is phosphorylated by pyruvate kinase to repress gene transcription. Here, we identify the protein phosphatase 1 (PP1), Glc7 as the enzyme that specifically dephosphorylates H3T11. We also characterize two novel Glc7-containing subcomplexes and reveal their roles in regulating gene expression upon glucose starvation. Specifically, the Glc7-Sen1 subcomplex dephosphorylates H3T11 to activate the transcription of autophagy-related genes. The Glc7-Rif1-Rap1 subcomplex dephosphorylates H3T11 to derepress the transcription of telomere-proximal genes. Upon glucose starvation, Glc7 expression is up-regulated and more Glc7 translocates into the nucleus to dephosphorylate H3T11, leading to induction of autophagy and derepressed transcription of telomere-proximal genes. Furthermore, the functions of PP1/Glc7 and the two Glc7-containing subcomplexes are conserved in mammals to regulate autophagy and telomere structure. Collectively, our results reveal a novel mechanism to regulate gene expression and chromatin structure in response to glucose availability.细胞如何调整基因表达以适应营养变化，这一机制目前仍不甚明晰。组蛋白H3T11（Histone H3T11）可被丙酮酸激酶磷酸化，进而阻遏基因转录。本研究鉴定出蛋白磷酸酶1（protein phosphatase 1, PP1）家族成员Glc7为特异性去磷酸化H3T11的酶。我们还表征了两种新型的含Glc7的亚复合物，并揭示了它们在葡萄糖饥饿条件下调控基因表达的功能。具体而言，Glc7-Sen1亚复合物通过去磷酸化H3T11，激活自噬相关基因的转录；Glc7-Rif1-Rap1亚复合物则通过去磷酸化H3T11，解除对端粒邻近基因转录的阻遏。葡萄糖饥饿状态下，Glc7的表达会上调，且更多Glc7易位进入细胞核以去磷酸化H3T11，进而诱导自噬并解除端粒邻近基因的转录阻遏。此外，PP1/Glc7及其两种含Glc7的亚复合物的功能在哺乳动物中保守存在，可调控自噬与端粒结构。综上，本研究揭示了一种响应葡萄糖可利用性、调控基因表达与染色质结构的全新机制。