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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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The trinity of ribosome-associated quality control and stress signaling for proteostasis and neuronal physiology

  • Park, Jumin (Department of Biological Sciences, Ulsan National Institute of Science and Technology) ;
  • Park, Jongmin (Department of Biological Sciences, Ulsan National Institute of Science and Technology) ;
  • Lee, Jongbin (Department of Biological Sciences, Ulsan National Institute of Science and Technology) ;
  • Lim, Chunghun (Department of Biological Sciences, Ulsan National Institute of Science and Technology)
  • Received : 2021.06.21
  • Accepted : 2021.08.24
  • Published : 2021.09.30
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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 triggered by ribosomal collisions, an indication of atypical translation. The ribosome-associated E3 ligase ZNF598 ubiquitinates small subunit proteins at the stalled ribosomes. A series of RQC factors are then recruited to dissociate and triage aberrant translation intermediates. Regulatory ribosomal 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 ribosome-associated kinases GCN2 and ZAKα, activating integrated stress response (ISR) and ribotoxic stress response (RSR), respectively. Hierarchical crosstalks among RQC, ISR, and RSR pathways are readily detectable since the collided ribosome is their common substrate for activation. Given the strong implications of RQC factors in neuronal physiology and neurological disorders, the interplay between RQC and ribosome-associated stress signaling may sustain proteostasis, adaptively determine cell fate, and contribute to neural pathogenesis. The elucidation of underlying molecular principles in relevant human diseases should thus provide unexplored therapeutic opportunities.

Keywords

Acknowledgement

This work was supported by grants from the Suh Kyungbae Foundation (SUHF-17020101); from the National Research Foundation funded by the Ministry of Science and Information & Communication Technology (MSIT), Republic of Korea (NRF2021R1A2C3011706; NRF-2021M3A9G8022960; NRF-2018 R1A5A1024261).

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