Silencing of ER and integrative stress responses in mistranslating mouse liver

We here studied proteostatic networks in liver with increased levels of ribosomal misreading, using mice expressing the Rps2-A226Y ribosomal ambiguity (ram) mutation. Surprisingly, we found that Rps2-A226Y mice lack activation of the eIF2 kinase/ATF4 pathway, the main component of the integrated stress response (ISR). In addition, we find a general downregulation of ER stress responses, possibly by the action of Sirtuin-1, as indicated by reduced mRNAs for lipogenic pathways and acute phase proteins. Downregulation of ER stress responses came along with activation of alternate proteostatic pathways including the proteasome and the formation of stress granules. mRNA expression profiles of liver from Rps2-A226Y mutant mice, expressed under a cre-lox system, and wild type (WT) ubiquitous Cre recombinase expressing mice at 15 months of age.本研究以表达Rps2-A226Y核糖体歧义（ram）突变的小鼠为模型，探究核糖体错读水平升高时肝脏内的蛋白质稳态网络（proteostatic networks）。令人意外的是，我们观测到Rps2-A226Y突变小鼠缺失整合应激反应（integrated stress response, ISR）的核心组分——eIF2激酶/ATF4通路的激活。此外，我们发现内质网应激（ER stress）反应普遍下调，该现象可能由沉默信息调节因子1（Sirtuin-1）介导，其佐证为脂肪生成通路及急性期蛋白的mRNA水平降低。内质网应激反应的下调伴随替代蛋白质稳态通路的激活，包括蛋白酶体通路及应激颗粒的形成。本数据集包含15月龄小鼠的肝脏mRNA表达谱，受试小鼠分为两组：一组为经Cre-lox重组系统（cre-lox system）介导的Rps2-A226Y突变小鼠，另一组为表达遍在性Cre重组酶的野生型（wild type, WT）小鼠。