Ribosome traffic: co-translational quality control and translation stress signaling

Abstract

Translating ribosomes accompany co-translational regulation of nascent polypeptide chains, including subcellular targeting, protein folding, and covalent modifications. Ribosome-associated quality control (RQC) is a co-translational surveillance mechanism that senses ribosomal collisions during atypical translation and triages aberrant translation intermediates. Regulatory ribosome stalling may occur on endogenous transcripts for quality gene expression, whereas ribosomal collisions are more globally induced by ribotoxic stressors such as translation inhibitors, ribotoxins, and UV radiation. The latter are sensed by the ribosome-associated kinases GCN2 and ZAKα, further activating integrated stress response (ISR) and ribotoxic stress response (RSR), respectively. Given the implication of RQC factors in neurological disorders, we hypothesize that the interplay between RQC and the translation stress pathways on the collided ribosome may sustain proteostasis, adaptively determine cell fate, and contribute to neural function and pathogenesis. I will discuss our approaches to 1) elucidate the molecular principles of RQC function and the translation stress signaling; and 2) demonstrate their physiological significance in the context of neurodegenerative diseases.