The space between notes: emerging roles for translationally silent ribosomes

Abstract

In addition to their central functions in translation, ribosomes can adopt inactive structures that are fully assembled yet devoid of mRNA. We describe how the abundance of idle eukaryotic ribosomes is influenced by a broad range of biological conditions spanning viral infection, nutrient deprivation, and developmental cues. Vacant ribosomes may provide a means to exclude ribosomes from translation while also shielding them from degradation, and the variable identity of factors that occlude ribosomes may impart distinct functionality. We propose that regulated changes in the balance of idle and active ribosomes provides a means to fine-tune translation. We provide an overview of idle ribosomes, describe what is known regarding their function, and highlight questions that may clarify their biological roles.

Keywords: eEF2K; hibernating ribosome; idle ribosome; mTOR; vacant ribosome.

Figure 1 –

Overview of idle ribosomes. (A) Structural model of a eukaryotic 80S ribosome showing mRNA (blue) three tRNA sites: A (aminoacyl, purple), P (peptidyl transfer, forest), and E (exit, gold). The model was created by aligning two unpublished 80S ribosome structures from rabbit that contain A- and P-, and P- and E-site tRNAs, respectively. tRNA binding sites are indicated by dashed lines throughout. (B) Stm1 (marine)-bound 80S ribosome from S. cerevisiae (PDB 4V88). (C) SERBP1 (marine) and eEF2 (hot pink)-bound 80S ribosome from mouse (PDB 7LS1). (D) 80S ribosome from S. cerevisiae bound to Lso2 (warm pink, PDB 6Z6K). (E) Human 80S ribosome bound to CCDC124 (warm pink, PDB 6Z6L). (F) Xenopus 80S ribosome bound to HABP4 (marine), eEF2 (hot pink), Dapl1 (teal), and eIF5A(green). Domains of eEF2 are not present in the structure. (PDB 7OYC). (G) Human 80S ribosome bound to SARS-CoV Nsp1 (purple), CCDC124 (warm pink), eRF1 (light blue), and ABCE1 (dark blue). Note that the C-terminus of CCDC124 is visible in this model (PDB 6ZME). tRNA-binding sites are not shown for clarity. (H) Microsporidian (Vairimorpha nectarix) 80S ribosome bound to MDF1 (gold) and MDF2 (violet purple, PDB 6RM3).

Figure 2 –

Proposed model for regulation of idle ribosomes. (A) Nutrient stress triggers mTOR inhibition and AMPK activation. Both events lead to activation of eEF2K, which may play a role in regulating the assembly of idle ribosomes. Nutrient stress also triggers ribophagy. The formation of idle ribosomes prevents excess turnover by creating a pool of ribosomes protected from degradation. (B) During recovery from nutrient deprivation, ribophagy is inhibited and idle ribosomes re-enter the translating pool, enabling a resumption of protein synthesis. (C) Loss of a ribosome-silencing factor (e.g. SERBP1) impairs the formation of idle ribosomes, leading to excess ribophagy during nutrient stress. (D) In this case, translational recovery is impaired due to the failure to preserve ribosomes.

Figure 3, Key Figure –

A representation of the regulation of silent ribosomes in different biological paradigms. To date, the orchestration of idle ribosomes has been shown to influence translation in three biological contexts. (A) In yeast, ribosome silencing factors preserve ribosomes during nutrient stress and enable efficient translational restart [31,46,47]. (B) Ribosomes are maintained in idle states in the pre-fertilization eggs of zebrafish and Xenopus. Idle ribosomes cease to be maintained as translation increases several hours post-fertilization [7]. (C) SARS-CoV-2 poisons host cell translation by inducing a range of idle ribosome complexes with a viral protein [52,62].