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Review
. 2020 Nov 4;48(19):10648-10661.
doi: 10.1093/nar/gkaa757.

Ribosomal stress-surveillance: three pathways is a magic number

Anna Constance Vind  1 , Aitana Victoria Genzor  1 , Simon Bekker-Jensen  1
Affiliations
Review

Ribosomal stress-surveillance: three pathways is a magic number

Anna Constance Vind et al. Nucleic Acids Res. .

Abstract

Cells rely on stress response pathways to uphold cellular homeostasis and limit the negative effects of harmful environmental stimuli. The stress- and mitogen-activated protein (MAP) kinases, p38 and JNK, are at the nexus of numerous stress responses, among these the ribotoxic stress response (RSR). Ribosomal impairment is detrimental to cell function as it disrupts protein synthesis, increase inflammatory signaling and, if unresolved, lead to cell death. In this review, we offer a general overview of the three main translation surveillance pathways; the RSR, Ribosome-associated Quality Control (RQC) and the Integrated Stress Response (ISR). We highlight recent advances made in defining activation mechanisms for these pathways and discuss their commonalities and differences. Finally, we reflect on the physiological role of the RSR and consider the therapeutic potential of targeting the sensing kinase ZAKα for treatment of ribotoxin exposure.

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Figures

Figure 1.
Figure 1.
The MAP kinase signaling network. (A) A vast array of stimuli can activate the MAP kinase network, including environmental stressors, inflammatory cytokines, growth factors and hormones. The canonical activation pattern of MAPK cascades begins with the stimulus-specific activation of a MAP kinase kinase kinase (MAP3K, green) that activates MAP kinase kinases (MAP2K, blue) that activates MAP kinases (MAPK, yellow). The cellular effects of MAP kinase signaling is mediated through the phosphorylation of a vast amount of effector proteins.
Figure 2.
Figure 2.
The translation elongation cycle and the ribotoxic stress response. (A) The ribosome can decode messenger RNA (mRNA) and translate it into protein in three sequential events; initiation, elongation and termination. Elongation is a three-step cycle that is repeated until the protein is fully synthesized, and the stop codon is reached. The key processive reactions are (i) the capture of amino acid loaded tRNA, (ii) transfer of the amino acid to the growing polypeptide chain and (iii) the release of vacant tRNA, which occur in the ribosomal A-, P- and E-sites, respectively. (B) Ribotoxic stress is sensed by the MAP3K ZAKα leading to activation of MAPKs p38 and JNK and inflammatory signaling. In case of strong and sustained signaling the cell will undergo regulated cell death. (C) Overview of ribosomal insults known to activate the RSR – see also Table 1. (D) Alternative splicing of the ZAK gene results in two different MAP3Ks, α and β, that share the first 11 exons followed by unique exons. ZAKα is an 800 amino acid protein containing a kinase domain, a leucine zipper (LZ), a sterile-alpha motif (SAM) and two ribosome-binding domains (RBDs). ZAKβ is a 455 amino acid protein that is identical to ZAKα in its N-terminus but has a unique C-terminus.
Figure 3.
Figure 3.
Ribosome collision and ribosome-associated quality control. (A) Translational stalling causes collision of ribosomes. This unique structure is recognized by the E3 ubiquitin ligase ZNF598 that promotes ubiquitination of the ribosomal proteins uS10, eS10 and uS3. Stalling on internal mRNA sequences is recognized by the ASC complex (Slh1 in yeast) which liberates the leading ribosome. The trailing ribosomes can then resume translation. Under certain circumstances, endonucleases cleave the mRNA between ribosomes resulting in ribosomes stalled on 3′end of the mRNA. This makes them accessible for splitting by the recycling factors Pelota, HBS1L and ABCE1 (Dom34, Hbs1 and Rli1 in yeast). The released mRNA is degraded by the 5′-3′ exoribonuclease Xrn1 and the exosome complex to prevent the aberrant mRNA from being translated again. While the 40S subunit is directly ready for recycling, the peptidyl-tRNA remains associated with the large ribosomal subunit. The obstructed 60S subunit is recognized by the RQC component NEMF (Rqc2 in yeast) that recruits the E3 ubiquitin ligase Listerin (Ltn1 in yeast) to the native peptide chain. NEMF/Rqc2 may employ ‘CAT-tailing’ to expose ribosome-buried and ubiquitinatable lysine residues in the native chain. Ubiquitination by listerin/Ltn1 recruits the ATPase VCP (Cdc48 in yeast), and once the nascent chain has been released from the tRNA by ANKZF1 (Vms1 in yeast), VCP can deliver the polypeptide to the proteasome, where it is degraded.
Figure 4.
Figure 4.
The integrated stress response. (A) The integrated stress response (ISR) converges on phosphorylation of eIF2α, resulting in global inhibition of cap-dependent mRNA translation. GCN2 is the relevant ISR-kinase upon translational arrest. Cap-independent pathways allow for the selective translation of ISR-specific mRNAs including ATF4. ATF4 is a transcription factor and effector of ISR that controls expression of stress response genes.
Figure 5.
Figure 5.
Sensing mechanisms and outcomes of ribosomal stress-surveillance pathways. Local translational arrest leads to collision of ribosomes, which is a signal for recruitment and activation of the RQC pathway sensor ZNF598. The RSR sensor ZAKα and the ISR sensor GCN2 may also be activated by recognition of this structure, or alternatively by sensing signals directly on stalled ribosomes. Once activated, the RQC pathway will attempt to rescue and recycle stalled ribosomes. The ISR pathway activates stress responses by inhibiting cap-dependent translation and facilitating selective translation of stress response proteins. The RSR pathway activates MAP kinase-driven stress responses and inflammatory signaling and may also mediate apoptotic signaling.
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