Ribo-Tweezer: rapid removal of ribosomal proteins reveals new layers of post-transcriptional gene-regulation

The ribosome is a ribozyme, but it may also act as a dynamic regulator of gene expression. Although ribosomal protein (RP) composition varies, dissecting the functional contributions of individual RPs beyond their housekeeping roles is challenging by the lack of tools for their selective manipulation in situ. Here, we developed Ribo-Tweezer, a degron-based system directly tethered to mature ribosomes that enables rapid, reversible, and selective depletion of specific RPs. Using Ribo-Tweezer, we find a new role for RACK1 in stem cell fate control via translational regulation of zinc-finger transcriptional networks and in turn LINE1 expression. This translation-transcription coupling provides a mechanism by which translation control is further amplified in gene regulation. Distinct translational programs induced by RPLP0 and RPLP1 depletion further demonstrate RP-specific regulatory functions in translating the genome. Together, these findings establish Ribo-Tweezer as a powerful platform that has illuminated selective functions for RPs in gene regulation.