iRQC, a surveillance pathway for 40S ribosomal quality control during mRNA translation initiation

Abstract

Highlights d RNF10 mediates site-specific ubiquitylation of uS3 and uS5 40S ribosomal proteins d Translation initiation inhibition induces ubiquitylation of uS3 and uS5 d Loss of USP10 results in elevated basal levels of uS3 and uS5 ubiquitylation d Constitutive ubiquitylation of uS3 and uS5 triggers degradation of the 40S subunit

Ribosome stalling is a signal for metabolic regulation by the ribotoxic stress response

“…We did, however, observe a mild increase in collision peaks as well as ribosomal recruitment of the collision sensors EDF1, 16 , 17 ubiquitinated RPS10, 18 , 19 and ubiquitinated RPS2 20 , 21 when cells were treated with EBSS ( Figures 1 G, S1 I, S1J, and S2 A). The collision-promoting effects of EBSS treatment were clearly exacerbated by GCN2 inhibition ( Figure 1 G), to an extent where the appearance of mono-ubiquitinated RPS10 could be observed by straight western blotting ( Figure 1 H).…”

Sensing of individual stalled 80S ribosomes by Fap1 for nonfunctional rRNA turnover

“…Since the codon recognition process is highly conserved and there are putative homologs of yeast 18S NRD factors in mammals (Garshott et al, 2021;Garzia et al, 2021;Kunz et al, 2000), it is conceivable that mammalian cells had to evolve similar systems that broaden the ability to handle diverse translational aberrancy.…”

Translational buffering by ribosome stalling in upstream open reading frames

“…Scanning ribosomes have been predicted to dissociate upon encountering stable secondary structures on the mRNA [ 83 ]. Collisions between scanning ribosomes and their subsequent dissociation have also been proposed in a model of initiation quality control [ 84 ]. This dissociation could serve to maintain the free pool of 40S ribosomal subunits while still allowing regulation of main ORF translation.…”

“…If we were to model cap-tethered initiation, strong uORF elongating ribosome stalls would eventually sever this connection, similar to how the cap-eIF-ribosome connection is severed during the usually longer translation of main ORFs [ 90 , 105 , 106 ]. It will also be interesting to consider the effect of cellular stress-reduced elongation rates [ 107 ] and increased re-initiation [ 108 ], both of which might regulate uORF-mediated buffering, as well as elongating ribosome dissociation through known quality control pathways [ 39 , 84 , 109 – 114 ]. Translation heterogeneity among isogenic mRNAs has been observed in several single-molecule translation studies [ 33 , 52 – 54 , 115 ].…”