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The trinity of ribosome-associated quality control and stress signaling for proteostasis and neuronal physiology

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Translating ribosomes accompany co-translational regulationof nascent polypeptide chains, including subcellular targeting,protein folding, and covalent modifications. Ribosome-associatedquality control (RQC) is a co-translational surveillance mechanismtriggered by ribosomal collisions, an indication of atypical translation. The ribosome-associated E3 ligase ZNF598 ubiquitinatessmall subunit proteins at the stalled ribosomes. A series of RQCfactors are then recruited to dissociate and triage aberrant translationintermediates. Regulatory ribosomal stalling may occur onendogenous transcripts for quality gene expression, whereas ribosomalcollisions are more globally induced by ribotoxic stressorssuch as translation inhibitors, ribotoxins, and UV radiation. Thelatter are sensed by ribosome-associated kinases GCN2 andZAKα, activating integrated stress response (ISR) and ribotoxicstress response (RSR), respectively. Hierarchical crosstalks amongRQC, ISR, and RSR pathways are readily detectable since thecollided ribosome is their common substrate for activation. Giventhe strong implications of RQC factors in neuronal physiologyand neurological disorders, the interplay between RQC andribosome-associated stress signaling may sustain proteostasis,adaptively determine cell fate, and contribute to neural pathogenesis. The elucidation of underlying molecular principles inrelevant human diseases should thus provide unexplored therapeuticopportunities.

Abstract

Translating ribosomes accompany co-translational regulationof nascent polypeptide chains, including subcellular targeting,protein folding, and covalent modifications. Ribosome-associatedquality control (RQC) is a co-translational surveillance mechanismtriggered by ribosomal collisions, an indication of atypical translation. The ribosome-associated E3 ligase ZNF598 ubiquitinatessmall subunit proteins at the stalled ribosomes. A series of RQCfactors are then recruited to dissociate and triage aberrant translationintermediates. Regulatory ribosomal stalling may occur onendogenous transcripts for quality gene expression, whereas ribosomalcollisions are more globally induced by ribotoxic stressorssuch as translation inhibitors, ribotoxins, and UV radiation. Thelatter are sensed by ribosome-associated kinases GCN2 andZAKα, activating integrated stress response (ISR) and ribotoxicstress response (RSR), respectively. Hierarchical crosstalks amongRQC, ISR, and RSR pathways are readily detectable since thecollided ribosome is their common substrate for activation. Giventhe strong implications of RQC factors in neuronal physiologyand neurological disorders, the interplay between RQC andribosome-associated stress signaling may sustain proteostasis,adaptively determine cell fate, and contribute to neural pathogenesis. The elucidation of underlying molecular principles inrelevant human diseases should thus provide unexplored therapeuticopportunities.

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