Ribosomal heterogeneity – a new inroad for pharmacological innovation

The paradigm of ribosome usage in protein translation has shifted from a stance proposed as scientists began to unpick the genetic code that each mRNA was partnered by its own, unique ribosome to a rapid reversal of this view that ribosomes are completely interchangeable and simply recruited to mRNAs from a completely homogenous cellular pool. Evidence that the ribosomal proteome, ribosomal gene transcriptome and ribosome protein and RNA modifications differ between cells and tissues points to the fact that ribosomes are heterogeneous in their composition and have a degree of specialisation in their function. It has also been posited that the tissue-specificity of ribosome diseases provides an indication of functional ribosome heterogeneity, but there are substantial caveats to this interpretation. Only now have proteomic technologies developed to a level enabling accurate stoichiometric comparison of the abundance of specific ribosomal proteins in actively translating ribosomes and to measure protein in non-denatured ribosomes. This poises the field for the provocation that ribosome heterogeneity offers a novel and powerful inroad for the pharmacological targeting of disease. Such ribosome-targeted treatments may extend beyond specific ribosomopathies through strategies such as targeting features of ribosomes that are unique to diseased cells, particularly cancer cells, or to activated immune cells, as well as augmenting the action of other drugs through weakening the production of new proteins in target tissues. We may also be able to harness the potential power in ribosome diversity and specialism to better tune synthetic biology for the production of pharmaceutical proteins.