Ribosomal Pauses during Translation and Proteostasis

Protein biosynthesis is essential to preserve cell homeostasis and it is a tightly regulated process composed of several phases. This chapter focuses on the translation elongation phase and the roles of the elongating ribosomes that in recent years have emerged as critical sensors to maintain proteostasis. Different internal or external cues can lead to ribosome pauses and the nature of the stall can promote reversible transient pauses or irreversible halts. The ribosome slowdown is sensed by the appearance of ribosome collisions which are recognized by the ubiquitin pathway and activate specialized machinery depending on the severity of the stress. In the case of drastic stops and severe ribosome collisions, the risk of generating toxic products leads to the removal of the faulty mRNA and nascent polypeptide. Failure of this activity has been linked to neurological disorders. In other cases, ribosomal stalls are beneficial for the proteostasis facilitating protein folding, subcellular targeting and protein complex formation. A key technological breakthrough to help elucidate these pathways has been the development of the ribosome profiling technology.