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. Overall design: 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.