tRNA ligase structure reveals kinetic competition between non-conventional mRNA splicing and mRNA decay

Peschek, Jirka; Walter, Peter

doi:10.7554/elife.44199

Cited by 31 publications

(29 citation statements)

References 60 publications

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“…It remains to be determined whether IRE1 plays a direct part in such clearing mechanisms by which cells rid themselves of defective mRNA. In the cellular environment, additional factors, including the Sec61 translocon 68 , or RNAbinding proteins such as Pumilio (Cairrao et al, co-submitted), could also help shield processed XBP1u against further decay and thereby permit exon ligation by RtcB 69 .…”

Section: Discussionmentioning

confidence: 99%

Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α promotes cancer-cell survival

A¹,

Ferri²,

Marsters³

et al. 2021

Preprint

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Eukaryotic IRE1 mitigates endoplasmic-reticulum (ER) stress by orchestrating the unfolded-protein response (UPR). IRE1 spans the ER membrane, and signals through a cytosolic kinase-endoribonuclease module. The endoribonuclease generates the transcription factor XBP1s by intron excision between similar RNA stem-loop endomotifs, and depletes select cellular mRNAs through regulated IRE1-dependent decay (RIDD). Paradoxically, mammalian RIDD seemingly targets only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1α-controlled mRNAs in human breast cancer cells, we discovered not only canonical endomotif-containing RIDD substrates, but also many targets lacking recognizable motifs-degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1α displayed two basic endoribonuclease modalities: endomotif-specific cleavage, minimally requiring dimers; and endomotif-independent promiscuous processing, requiring phospho-oligomers. An oligomer-deficient mutant that did not support RIDDLE failed to rescue cancer-cell viability. These results link IRE1α oligomers, RIDDLE, and cell survival, advancing mechanistic understanding of the UPR.

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Section: Discussionmentioning

confidence: 99%

Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α promotes cancer-cell survival

A¹,

Ferri²,

Marsters³

et al. 2021

Preprint

Self Cite

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“…From our model, we also predict that upon overcoming ER stress conditions, Pumilio phosphorylation levels will be reduced, either due to the activity of phosphatases and/or due to Ire1 dephosphorylation and attenuation 61 . At this stage, Pumilio’s protective role over Xbp1 mRNA may subside, presumably making the transcript more vulnerable to the action of the mRNA decay machinery and the ribosome-associated quality control, as previously shown for Hac1 62 . This regulatory step may avoid an accumulation of Xbp1 spliced under non stress conditions, which could be detrimental for cellular homeostasis.…”

Section: Discussionmentioning

confidence: 58%

Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay

Cairrão

A³

et al. 2021

Preprint

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The unfolded protein response (UPR) maintains homeostasis of the endoplasmic reticulum (ER). Residing in the ER membrane, the UPR mediator Ire1 deploys its cytoplasmic kinase-endoribonuclease domain to activate the key UPR transcription factor Xbp1 through non-conventional splicing of Xbp1 mRNA. Ire1 also degrades diverse ER-targeted mRNAs through regulated Ire1-dependent decay (RIDD), but how it spares Xbp1 mRNA from this decay is unknown. We identified binding sites for the RNA-binding protein Pumilio in the 3 UTR Drosophila Xbp1. In the developing Drosophila eye, Pumilio bound both the Xbp1unspliced and Xbp1spliced mRNAs, but only Xbp1spliced was stabilized by Pumilio. Furthermore, Pumilio displayed Ire1 kinase-dependent phosphorylation during ER stress, which was required for its stabilization of Xbp1spliced. Human IRE1 could directly phosphorylate Pumilio, and phosphorylated Pumilio protected Xbp1spliced mRNA against RIDD. Thus, Ire1-mediated phosphorylation enables Pumilio to shield Xbp1spliced from RIDD. These results uncover an important and unexpected regulatory link between an RNA-binding protein and the UPR.

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“…At this step, the tRNA fragments would be in competition among three different fates: completion of endonucleolytic cleavage by the SEN complex; healing and religation by the tRNA ligase (Trl1); or decay by exonucleases. This type of model was recently proposed as a mechanism regulating decay of HAC1 mRNA, encoding a major regulator of the unfolded protein response; this mRNA is spliced by a similar mechanism to tRNA, using Ire1 endonuclease and tRNA ligase (Sidrauski et al 1996;Sidrauski and Walter 1997), and ligation of its cleavage products is in competition with decay mediated by Xrn1 (Cherry et al 2019;Peschek and Walter 2019). Future experiments should cast light on the mechanism by which the MPD pathway monitors pre-tRNA quality and mediates decay.…”

Section: Discussionmentioning

confidence: 99%

Mutations in the anticodon stem of tRNA cause accumulation and Met22-dependent decay of pre-tRNA in yeast

Payea

Hauke

Zoysa

et al. 2019

RNA

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During tRNA maturation in yeast, aberrant pre-tRNAs are targeted for 3 ′ ′ ′ ′ ′ -5 ′ ′ ′ ′ ′ degradation by the nuclear surveillance pathway, and aberrant mature tRNAs are targeted for 5 ′ ′ ′ ′ ′ -3 ′ ′ ′ ′ ′ degradation by the rapid tRNA decay (RTD) pathway. RTD is catalyzed by the 5 ′ ′ ′ ′ ′ -3 ′ ′ ′ ′ ′ exonucleases Xrn1 and Rat1, which act on tRNAs with an exposed 5 ′ ′ ′ ′ ′ end due to the lack of certain body modifications or the presence of destabilizing mutations in the acceptor stem, T-stem, or tRNA fold. RTD is inhibited by mutation of MET22, likely due to accumulation of the Met22 substrate adenosine 3 ′ ′ ′ ′ ′ ,5 ′ ′ ′ ′ ′ bis-phosphate, which inhibits 5 ′ ′ ′ ′ ′ -3 ′ ′ ′ ′ ′ exonucleases. Here we provide evidence for a new tRNA quality control pathway in which intron-containing pre-tRNAs with destabilizing mutations in the anticodon stem are targeted for Met22-dependent pre-tRNA decay (MPD). Multiple SUP4 οc anticodon stem variants that are subject to MPD each perturb the bulge-helix-bulge structure formed by the anticodon stem-loop and intron, which is important for splicing, resulting in substantial accumulation of end-matured unspliced pre-tRNA as well as pre-tRNA decay. Mutations that restore exon-intron structure commensurately reduce pre-tRNA accumulation and MPD. The MPD pathway can contribute substantially to decay of anticodon stem variants, since pre-tRNA decay is largely suppressed by removal of the intron or by restoration of exon-intron structure, each also resulting in increased tRNA levels. The MPD pathway is general as it extends to variants of tRNA Tyr(GUA) and tRNA Ser(CGA) . These results demonstrate that the integrity of the anticodon stem-loop and the efficiency of tRNA splicing are monitored by a quality control pathway.

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tRNA ligase structure reveals kinetic competition between non-conventional mRNA splicing and mRNA decay

Cited by 31 publications

References 60 publications

Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α promotes cancer-cell survival

Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α promotes cancer-cell survival

Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay

Mutations in the anticodon stem of tRNA cause accumulation and Met22-dependent decay of pre-tRNA in yeast

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