According to ample experimental evidence, decreasing protein synthesis by inhibiting mTORC1 increases lifespan of most model animals. mTORC1 is a well-studied translation regulator of a selected pool of transcripts bearing terminal oligopyrimidine motif. However, mTORC1 is involved in the regulation of various cellular processes and the causality between translation and lifespan is unclear. In this study, we were driven by the idea of perturbing protein synthesis directly without triggering mTOR signaling. We employed an in vivo siRNA treatment to suppress the translation elongation factor 2 (EEF2) in the liver of adult mice for the duration of up to 2 weeks. Proteomics and ribosome profiling assays showed strong translational upregulation of ribosomal proteins, which are known to be regulated by mTOR. At the same time, the branch of mTOR pathway responsible for translation regulation was not activated. We concluded that the upregulation of ribosomal transcripts occurred via the passive mTOR-independent mechanism. Impaired elongation sequesters ribosomes on mRNA and shortage of free ribosomes leads to the preferential translation of transcripts with high initiation rate such as ribosomal proteins. SOURCE: Maxim Gerashchenko (mgerashchenko@bwh.harvard.edu) -  Brigham and Women's Hospital

Pluto Bioinformatics

GSE136091: Long-term EEF2 depletion in mouse liver leads to mTOR-independent translational upregulation of ribosomal genes