4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay

Weber, Ramona; Chung, Min-Yi; Keskeny, Csilla; Zinnall, Ulrike; Landthaler, Markus; Valkov, Eugene; Izaurralde, Elisa; Igreja, Cátia

doi:10.1016/j.celrep.2020.108262

Cited by 46 publications

(49 citation statements)

References 105 publications

(146 reference statements)

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“…Each of the mammalian studies established a clear role for GI-GYF2/4E2 in translational repression on the problematic mRNAs tested with no evidence for a role in mRNA degradation (Hickey et al, 2020;Juszkiewicz et al, 2020a;Sinha et al, 2020); however, a recent genome-wide analysis of GIGYF2 protein function argues for a broader role for these proteins in mediating mRNA decay (Weber et al, 2020). Further targeted experiments will be required to sort through some of the differences and specificities defined in these many studies.…”

Section: Qc On Problematic Mrnas With Disruptions Within the Orfmentioning

confidence: 99%

Ribosome states signal RNA quality control

2021

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Eukaryotic cells integrate multiple quality control (QC) responses during protein synthesis in the cytoplasm. These QC responses are signaled by slow or stalled elongating ribosomes. Depending on the nature of the delay, the signal may lead to translational repression, messenger RNA decay, ribosome rescue, and/or nascent protein degradation. Here, we discuss how the structure and composition of an elongating ribosome in a troubled state determine the downstream quality control pathway(s) that ensue. We highlight the intersecting pathways involved in RNA decay and the crosstalk that occurs between RNA decay and ribosome rescue.

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Section: Qc On Problematic Mrnas With Disruptions Within the Orfmentioning

confidence: 99%

Ribosome states signal RNA quality control

2021

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“…RQC substrate, consecutive Lys AAA codons, does not promote apparent mRNA decay in vertebrates (Juszkiewicz and Hegde, 2017), whereas recruitment of the Znf598-4EHP-GIGYF1/2 complex on paused ribosomes promotes mRNA decay (Weber et al, 2020).…”

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confidence: 94%

“…It is therefore possible that the yeast Not3 ortholog CNOT3 anchors the CCR4-NOT complex to the slow ribosome via the E site in vertebrates (Buschauer et al, 2020;Collart and Panasenko, 2017). The ubiquitination site(s) on the ribosome and downstream NGD effectors are also conserved in vertebrates (D'Orazio et al, 2019;Garzia et al, 2017;Ikeuchi et al, 2019;Juszkiewicz et al, 2020Juszkiewicz et al, , 2018Juszkiewicz and Hegde, 2017;Matsuo et al, 2017;Sundaramoorthy et al, 2017;Weber et al, 2020). Future studies will reveal the conservation and biological function of codon-mediated decay and NGD.…”

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confidence: 99%

Transient ribosome slowdown at the decoding step triggers mRNA degradation independent of Znf598 in zebrafish

Mishima

Han

Kimura

et al. 2021

Preprint

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The control of mRNA stability plays a central role in regulating gene expression patterns. Recent studies have revealed that codon composition in the open reading frame (ORF) determines mRNA stability in multiple organisms. Based on genome-wide correlation approaches, this previously unrecognized role of the genetic code is attributable to the kinetics of the codon-decoding process by the ribosome. However, complementary experimental analysis is required to define the codon effects on mRNA stability apart from the related cotranslational mRNA decay pathways such as those triggered by aberrant ribosome stalls. In the current study, we performed a set of reporter-based analyses to define codon-mediated mRNA decay and ribosome stall-dependent mRNA decay in zebrafish embryos. Our analysis showed that the effect of codons on mRNA stability stems from the decoding process, independent of Znf598 and stall-dependent mRNA decay. We propose that codon-mediated mRNA decay is triggered by transiently slowed ribosomes engaging in a productive translation cycle in zebrafish embryos.

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“…The specificity of 4EHP-mediated translational repression is thought to be imparted by the GYF domain of the GIGYF proteins, which serves as an adaptor to bridge RNA-binding proteins to 4EHP (Morita et al 2012;Fu et al 2016;Schopp et al 2017;Weber et al 2020).…”

Section: Introductionmentioning

confidence: 99%

Molecular basis for GIGYF-TNRC6 complex assembly in miRNA-mediated translational repression

Sobti

Mead

Igreja

et al. 2021

Preprint

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The GIGYF proteins associate with 4EHP and RNA-associated proteins to elicit transcript-specific translational repression. However, the mechanism by which the GIGYF1/2-4EHP complex is recruited to its target transcripts remain unclear. Here we report the crystal structures of the GYF domains from GIGYF1 and GIGYF2 in complex with proline-rich sequences from miRISC-binding proteins TNRC6C and TNRC6A, respectively. The TNRC6 proline-rich motifs bind to a conserved array of aromatic residues on the surface of the GIGYF1/2 GYF domain, bridging 4EHP to Argonaute-miRNA mRNA targets. Our structures also reveal a phenylalanine residue conserved from yeast to human GYF domains that contributes to GIGYF2 thermostability. The molecular details we outline here are likely to be conserved between GIGYF1/2 and other RNA-binding proteins to elicit 4EHP-mediated repression in different biological contexts.

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4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay

Abstract: Highlights d 4EHP and GIGYF1/2 induce co-translational mRNA decay d Targeted transcripts are characterized by ribosome pausing and collision d mRNA decay requires ribosome pausing, DDX6, and partially ZNF598 d Identified mRNAs encode secreted and membrane-bound proteins or tubulin subunits

Cited by 46 publications

References 105 publications

Ribosome states signal RNA quality control

Ribosome states signal RNA quality control

Transient ribosome slowdown at the decoding step triggers mRNA degradation independent of Znf598 in zebrafish

Molecular basis for GIGYF-TNRC6 complex assembly in miRNA-mediated translational repression

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