Rebirth of the translational machinery: The importance of recycling ribosomes

Abstract

Translation of the genetic code occurs in a cycle where ribosomes engage mRNAs, synthesize protein, and then disengage in order to repeat the process again. The final part of this process-ribosome recycling, where ribosomes dissociate from mRNAsinvolves a complex molecular choreography of specific protein factors to remove the large and small subunits of the ribosome in a coordinated fashion. Errors in this process can lead to the accumulation of ribosomes at stop codons or translation of downstream open reading frames (ORFs). Ribosome recycling is also critical when a ribosome stalls during the elongation phase of translation and must be rescued to allow continued translation of the mRNA. Here we discuss the molecular interactions that drive ribosome recycling, and their regulation in the cell. We also examine the consequences of inefficient recycling with regards to disease, and its functional roles in synthesis of novel peptides, regulation of gene expression, and control of mRNA-associated proteins. Alterations in ribosome recycling efficiency have the potential to impact many cellular functions but additional work is needed to understand how this regulatory power is utilized.

Principles, mechanisms, and biological implications of translation termination–reinitiation

“…These later steps of recycling are primarily performed by eIF2D (Tma64 in yeast; also referred to in many previous studies as Ligatin) or a heterodimer consisting of multiple copies in T-cell lymphoma-1 (MCT-1; Tma22 in yeast) and density regulated protein (DENR; Tma20 in yeast) (Skabkin et al 2010;Hellen 2018;Young et al 2018;Bohlen et al 2020b;Gaikwad et al 2021;Young et al 2021;Young and Guydosh 2022). The DENR/MCT-1 heterodimer resembles eIF2D, with MCT-1 and DENR sharing significant homology with the N-and C-terminal portions of eIF2D, respectively (Lomakin et al 2017;Weisser et al 2017).…”

“…Rather than presenting a comprehensive review of relevant literature, we briefly compare these three scenarios with an eye towards spotting common themes hinting at underlying principles that link these seemingly disparate scenarios. We put reinitiation into the context of the canonical translation cycle, including recent studies that have clarified the roles of many recycling factors and their contributions to reinitiation (Ahmed et al 2018;Young and Guydosh 2019;Bohlen et al 2020b;Young et al 2021;Young and Guydosh 2022). We also compare the distinct mechanisms and functional outcomes between reinitiation and other types of non-canonical translation events.…”

Proteostasis regulation through ribosome quality control and no‐go‐decay

“…The leading and colliding ribosomes are rescued and returned to the pool of ribosomes. The Dom34‐Hbs1 (Pelota‐Hbs1L) rescues the colliding ribosome after the endonucleolytic cleavage event, whereas the leading ribosome is dissociated by the RQT complex (Simms et al, 2017; Sitron et al, 2017; Tsuboi et al, 2012; Young & Guydosh, 2022). The primary determinant of the route of ribosome disassembly is the presence of 3′‐mRNA emerging from the lead ribosome that a trailing of 80S can follow.…”

“…RQC encompasses mRNA surveillance and protein quality control to repress their translation and triggers the degradation of problematic mRNAs and truncated nascent peptides (Bengtson & Joazeiro, 2010; D'Orazio et al, 2019; Ito‐Harashima et al, 2007; Juszkiewicz & Hegde, 2017; Matsuo et al, 2017; Simms et al, 2017; Sitron et al, 2017; Tomomatsu et al, 2023; Veltri et al, 2022). Translation and ribosome biogenesis are energy‐expensive processes, as they require the coordination of rRNA transcription, modification of rRNAs, and translation of ribosomal RNAs to achieve ribosome assembly (Hershey et al, 2019; Holcik & Sonenberg, 2005; Li et al, 2009; Young & Guydosh, 2022). Thus, RQC also enables cells to rescue and recycle ribosomes from problematic mRNAs to make them available to translate appropriate mRNAs (Ikeuchi, Tesina, et al, 2019; Juszkiewicz et al, 2018; Juszkiewicz & Hegde, 2017; Matsuo et al, 2017; Sitron et al, 2017; Sundaramoorthy et al, 2017).…”

A conserved class of viral RNA structures regulate translation reinitiation through dynamic ribosome interactions

“…In the second phase, the ribosome elongates through the coding region until it reaches an in-frame stop codon and terminates, releasing the protein product (Dever and Green, 2012; Hellen, 2018). The ribosome is then recycled for another round of translation by sequential removal of the large (60S) ribosomal subunit, transfer RNA (tRNA), and the small (40S) ribosomal subunit from the mRNA (Young and Guydosh, 2022). However, under specific circumstances this final recycling step can be altered: successful termination and peptide release but incomplete ribosome recycling leads to translation “re-initiation.” In reinitiation, mRNA sequence downstream of the termination codon is translated by the same ribosome as the upstream main ORF, leading to a second protein product expressed from a single mRNA (Gunisova et al, 2018; Sherlock et al, 2023; Skabkin et al, 2013).…”