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Review
. 2016 Jan;23(1):7-15.
doi: 10.1038/nsmb.3147.

Ribosome-associated protein quality control

Onn Brandman, Ramanujan S Hegde
Review

Ribosome-associated protein quality control

Onn Brandman et al. Nat Struct Mol Biol. 2016 Jan.

Abstract

Protein synthesis by the ribosome can fail for numerous reasons including faulty mRNA, insufficient availability of charged tRNAs and genetic errors. All organisms have evolved mechanisms to recognize stalled ribosomes and initiate pathways for recycling, quality control and stress signaling. Here we review the discovery and molecular dissection of the eukaryotic ribosome-associated quality-control pathway for degradation of nascent polypeptides arising from interrupted translation.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Causes of aberrant translation elongation. Top, normal translation involves initiation, elongation through the coding region, termination and recycling of ribosomal subunits. Bottom, four different situations that can cause ribosomal stalling before the stop codon is reached. In each case, stalling can initiate one or more downstream pathways that facilitate stall resolution and cellular adaptation. Figure adapted with permission from ref. , Elsevier. aa-tRNA, aminoacyl-tRNA; ORF, open reading frame.
Figure 2
Figure 2
Primary steps and factors of ribosome-associated quality control. A stalled ribosome is recognized and acted upon by ribosome-recycling factors that split the ribosomal subunits. Removal of the 40S subunit exposes the peptidyl-tRNA and intersubunit interface on the 60S subunit. These cues are recognized by RQC components, whose assembly on the 60S subunit permits ubiquitination of nascent polypeptides. The polyubiquitinated complex is then disassembled, thus allowing recycling of the factors and degradation of the nascent chain. Shown below are the homologous yeast and mammalian factors implicated at each step. Question marks indicate factors implicated by homology whose direct role remains to be examined experimentally. Figure adapted with permission from ref. , Elsevier.
Figure 3
Figure 3
Working model for recognition of a stalled ribosome by recycling factors. Top left (green background), a simplified translation elongation cycle is shown. A translating ribosome in the nonrotated state (center) engages the tRNA–eEF1A–GTP ternary complex in response to a sense codon in the A site. Codon recognition by the tRNA triggers GTP hydrolysis by eEF1A, release of the latter from the ribosome and accommodation of the tRNA to catalyze peptide-bond formation. The ribosome is then translocated by one codon via the action of eEF2 to complete the cycle. Top right (white background), when a stop codon enters the A site, it is recognized by an eRF1–eRF3–GTP complex that functions analogously to the elongation complex. Upon accommodation of eRF1, the ATPase Rli1 (ABCE1 in mammals) is recruited, and peptidyl-tRNA is hydrolyzed, thus releasing the nascent protein. The ribosomal subunits are separated by the action of the eRF1–Rli1 complex. Bottom (pink background), failure to be engaged by either the eEF1 or eRF1 complex permits ‘default’ engagement by the Dom34–Hbs1–GTP complex, which does not exhibit codon specificity. These factors act similarly to the homologous eRF1–eRF3 complex, with the exception that Dom34 (Pelota in mammals) does not catalyze peptidyl-tRNA hydrolysis. Thus, subunit separation results in a 60S–peptidyl-tRNA complex that is targeted by the RQC. T, GTP; D, GDP; E, exit tunnel.
Figure 4
Figure 4
Steps of RQC assembly on 60S–peptidyl-tRNA complexes. (a) Upon subunit separation, the exposed interface of the 60S subunit has high affinity for both the 40S subunit and the factor NEMF (Rqc2 in yeast). NEMF binding via both the tRNA and 60S interface effectively precludes 40S reassociation and facilitates binding of Listerin (Ltn1 in yeast). Listerin’s RING domain is positioned near the polypeptide exit tunnel, thus facilitating nascent-chain ubiquitination. Figure adapted with permission from ref. , Elsevier. (b) Intersubunit view of the assembled mammalian 60S–peptidyl-tRNA–RQC complex. Teal, NEMF; purple, P-site tRNA; orange, Listerin; gray, ribosome. The direct interaction between NEMF and Listerin is shown. (c) Cutaway view illustrating the direct recognition of P-site tRNA by NEMF and the proximity of Listerin to the polypeptide exit tunnel over 100 Å away.
Figure 5
Figure 5
CAT-tail formation by Rqc2p. (a) Architecture of the Rqc2–60S complex bound to both A- and P-site tRNAs, illustrating that the two amino acid–attachment sites are juxtaposed at the peptidyl transferase center (PTC). (b) Recognition of the A-site tRNA via the anticodon loop and D loop is thought to provide specificity for alanine and threonine tRNAs. (c) A speculative elongation cycle in which a 60S–RQC complex with P-site tRNA interacts with a threonine- or alanine-charged tRNA in the A site. This brings the charged amino acid into the peptidyl transferase center, thereby facilitating attack of the ester bond (arrow) on the peptidyl-tRNA. Transfer of the nascent chain to the A-site tRNA frees the P-site tRNA, which over time dissociates. The A-site peptidyl-tRNA can then engage the P site, which might be a higher-affinity site, to complete the cycle. Figure adapted with permission from ref. , AAAS.
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