The integrated stress response regulates 18S nonfunctional rRNA decay in mammals

Abstract

18S nonfunctional rRNA decay (NRD) detects and eliminates translationally nonfunctional 18S rRNA. Although this process is critical for ribosome quality control, the mechanisms underlying nonfunctional 18S rRNA turnover remain elusive, particularly in mammals. Here, we show that mammalian 18S NRD initiates through the integrated stress response (ISR) via GCN2. Nonfunctional 18S rRNA induces translational arrest at start sites. Biochemical analyses demonstrate that ISR activation limits translation initiation and attenuates collisions between scanning 43S preinitiation complexes and stalled nonfunctional ribosomes. The ISR promotes 18S NRD and 40S ribosomal protein turnover by RNF10-mediated ubiquitination. Ultimately, RIOK3 binds the resulting ubiquitinated 40S subunits and facilitates 18S rRNA decay. Overall, mammalian 18S NRD acts through GCN2, followed by ubiquitin-dependent 18S rRNA degradation involving the ubiquitin E3 ligase RNF10 and the atypical protein kinase RIOK3. These findings establish a dynamic feedback mechanism by which the GCN2-RNF10-RIOK3 axis surveils ribosome functionality at the translation initiation step. • Decoding-incompetent ribosomes activate the integrated stress response (ISR) via GCN2 • The ISR reduces collisions between 43S PICs and decoding-incompetent monosomes • The ISR enhances 18S NRD through RNF10-mediated ubiquitination • RIOK3 binds ubiquitinated 40S subunits to facilitate 18S rRNA decay To maintain translational fidelity, cells degrade decoding-incompetent ribosomes through the 18S nonfunctional rRNA decay (NRD) pathway. Coria et al. demonstrate that the concerted actions of GCN2, RNF10, and RIOK3 lead to a block in translation initiation, ubiquitination of faulty ribosomes, and, ultimately, the degradation of nonfunctional 18S rRNA.

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