Nuclear mRNA degradation tunes the gain of the unfolded protein response in Saccharomyces cerevisiae

Sarkar, Debasish; Paira, Sunirmal; Das, Biswadip

doi:10.1093/nar/gkx1160

Cited by 22 publications

(26 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to its role in HAC1 exon ligation, Trl1 is required to relieve translational attenuation of HAC1 s by an unknown mechanism (Mori et al, 2010). In cells expressing the T4 bacteriophage RNA repair enzymes PNK and RNL1 in lieu of TRL1 , ligated HAC1 molecules contained single nucleotide deletions from the 3′-terminus of the 5′-exon, indicating that a 3′→5′ exonucleolytic activity acts on the cleaved 5′-exon (Schwer et al, 2004) and nuclear 3′→5′ decay of HAC1 u liberates the 3′-BE, tuning the activation potential of the UPR (Sarkar et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Multiple decay events target HAC1 mRNA during splicing to regulate the unfolded protein response

Cherry

Peach

Hesselberth

2019

eLife

View full text Add to dashboard Cite

In the unfolded protein response (UPR), stress in the endoplasmic reticulum (ER) activates a large transcriptional program to increase ER folding capacity. During the budding yeast UPR, Ire1 excises an intron from the HAC1 mRNA and the exon products of cleavage are ligated, and the translated protein induces hundreds of stress-response genes. Using cells with mutations in RNA repair and decay enzymes, we show that phosphorylation of two different HAC1 splicing intermediates is required for their degradation by the 5′→3′ exonuclease Xrn1 to enact opposing effects on the UPR. We also found that ligated but 2′-phosphorylated HAC1 mRNA is cleaved, yielding a decay intermediate with both 5′- and 2′-phosphates at its 5′-end that inhibit 5′→3′ decay and suggesting that Ire1 degrades incompletely processed HAC1. These decay events expand the scope of RNA-based regulation in the budding yeast UPR and have implications for the control of the metazoan UPR.

show abstract

Section: Introductionmentioning

confidence: 99%

Multiple decay events target HAC1 mRNA during splicing to regulate the unfolded protein response

Cherry

Peach

Hesselberth

2019

eLife

View full text Add to dashboard Cite

show abstract

“…In addition to its role in HAC1 exon ligation, Trl1 is required to relieve translational attenuation of HAC1 s by an unknown mechanism (Mori et al, 2010) . In cells expressing the T4 bacteriophage RNA repair enzymes PNK and RNL in lieu of TRL1 , ligated HAC1 molecules contained single nucleotide deletions from the 3′-terminus of the 5′-exon, indicating that a 3′→5′ exonucleolytic activity acts on the cleaved 5′-exon (Schwer et al, 2004) and nuclear decay of HAC1 u liberates the 3′-BE, tuning the activation potential of the UPR (Sarkar et al, 2018) .…”

Section: Introductionmentioning

confidence: 99%

Multiple decay events target HAC1 mRNA during splicing to regulate the unfolded protein response

Cherry

Peach

Hesselberth

2018

Preprint

View full text Add to dashboard Cite

In the unfolded protein response (UPR), protein-folding stress in the endoplasmic reticulum (ER) activates a large transcriptional program to increase ER folding capacity. During the budding yeast UPR, the trans-ER-membrane kinase-endoribonuclease Ire1 excises an intron from the HAC1 mRNA and the exon cleavage products are ligated and translated to a transcription factor that induces hundreds of stress-response genes. HAC1 cleavage by Ire1 is thought to be the rate limiting step of its processing. Using cells with mutations in RNA repair and decay enzymes, we show that phosphorylation of two different HAC1 splicing intermediates by Trl1 RNA 5′-kinase is required for their degradation by the 5′→3′ exonuclease Xrn1 to enact opposing effects on the UPR. Kinase-mediated decay (KMD) of cleaved HAC1 3′-exon competes with its ligation to limit productive splicing and suppress the UPR, whereas KMD of the excised intron activates HAC1 translation, likely by relieving an inhibitory base-pairing interaction between the intron and 5′-untranslated region. We also found that ligated but 2′-phosphorylated HAC1 mRNA is endonucleolytically cleaved, yielding a KMD intermediate with both 5′-and 2′-phosphates at its 5′-end that inhibit 5′→3′ decay, and suggesting that Ire1 initiates the degradation of incompletely processed HAC1 s to proofread ligation or attenuate the UPR. These multiple decay events expand the scope of RNA-based regulation in the budding yeast UPR and may have implications for the control of the metazoan UPR by mRNA processing.

show abstract

“…It has been demonstrated in different studies that the inability to induce the UPR system or downstream proteins results in a strong sensitivity against ER stress-inducing agents such as TM [ 41 , 42 , 43 ]. To test whether the tRNA modification mutants display altered TM sensitivity due to the reduced UPR induction we conducted liquid growth inhibition assays.…”

Section: Resultsmentioning

confidence: 99%

Unfolded Protein Response Suppression in Yeast by Loss of tRNA Modifications

Bruch

Klassen

Schaffrath

2018

Genes

View full text Add to dashboard Cite

Modifications in the anticodon loop of transfer RNAs (tRNAs) have been shown to ensure optimal codon translation rates and prevent protein homeostasis defects that arise in response to translational pausing. Consequently, several yeast mutants lacking important anticodon loop modifications were shown to accumulate protein aggregates. Here we analyze whether this includes the activation of the unfolded protein response (UPR), which is commonly triggered by protein aggregation within the endoplasmic reticulum (ER). We demonstrate that two different aggregation prone tRNA modification mutants (elp6 ncs2; elp3 deg1) lacking combinations of 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U: elp3; elp6; ncs2) and pseudouridine (Ψ: deg1) reduce, rather than increase, splicing of HAC1 mRNA, an event normally occurring as a precondition of UPR induction. In addition, tunicamycin (TM) induced HAC1 splicing is strongly impaired in the elp3 deg1 mutant. Strikingly, this mutant displays UPR independent resistance against TM, a phenotype we found to be rescued by overexpression of tRNAGln(UUG), the tRNA species usually carrying the mcm5s2U34 and Ψ38 modifications. Our data indicate that proper tRNA anticodon loop modifications promote rather than impair UPR activation and reveal that protein synthesis and homeostasis defects in their absence do not routinely result in UPR induction but may relieve endogenous ER stress.

show abstract

Nuclear mRNA degradation tunes the gain of the unfolded protein response in Saccharomyces cerevisiae

Cited by 22 publications

References 77 publications

Multiple decay events target HAC1 mRNA during splicing to regulate the unfolded protein response

Multiple decay events target HAC1 mRNA during splicing to regulate the unfolded protein response

Multiple decay events target HAC1 mRNA during splicing to regulate the unfolded protein response

Unfolded Protein Response Suppression in Yeast by Loss of tRNA Modifications

Contact Info

Product

Resources

About