Rocaglates Induce Gain-of-Function Alterations to eIF4A and eIF4F

Chu, Jennifer; Zhang, Wenhan; Cencic, Regina; O‘Connor, Patrick B F; Robert, Françis; Devine, William G.; Selznick, Asher; Henkel, Thomas; Merrick, William C.; Brown, Lauren E.; Baranov, Pavel V.; Porco, John A.; Pelletier, Jerry

doi:10.1016/j.celrep.2020.02.002

Cited by 52 publications

(90 citation statements)

References 20 publications

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“…We also found poor correlation with datasets obtained with rocaglates (Roc A and silvestrol)—an unsurprising result, given the completely different mechanism of action between rocaglates and Hipp. Rocaglates act as interfacial inhibitors and produce a gain-of-function complex, where eIF4A and eIF4F are clamped onto RNA, and these complexes act as steric barriers to scanning ribosomes, leading to a global decrease in available eIF4F levels ( 16 , 17 ). Rocaglates are thus not suited to define cellular mRNAs whose translation are most sensitive to eIF4A1 fluctuations.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of hippuristanol-resistant mutants reveals eIF4A1 dependencies within mRNA 5′ leader regions

Steinberger

Shen

Kiniry

et al. 2020

Nucleic Acids Research

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Hippuristanol (Hipp) is a natural product that selectively inhibits protein synthesis by targeting eukaryotic initiation factor (eIF) 4A, a DEAD-box RNA helicase required for ribosome recruitment to mRNA templates. Hipp binds to the carboxyl-terminal domain of eIF4A, locks it in a closed conformation, and inhibits its RNA binding. The dependencies of mRNAs for eIF4A during initiation is contingent on the degree of secondary structure within their 5′ leader region. Interest in targeting eIF4A therapeutically in cancer and viral-infected settings stems from the dependencies that certain cellular (e.g. pro-oncogenic, pro-survival) and viral mRNAs show towards eIF4A. Using a CRISPR/Cas9-based variomics screen, we identify functional EIF4A1 Hipp-resistant alleles, which in turn allowed us to link the translation-inhibitory and cytotoxic properties of Hipp to eIF4A1 target engagement. Genome-wide translational profiling in the absence or presence of Hipp were undertaken and our validation studies provided insight into the structure-activity relationships of eIF4A-dependent mRNAs. We find that mRNA 5′ leader length, overall secondary structure and cytosine content are defining features of Hipp-dependent mRNAs.

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Section: Discussionmentioning

confidence: 99%

Identification and characterization of hippuristanol-resistant mutants reveals eIF4A1 dependencies within mRNA 5′ leader regions

Steinberger

Shen

Kiniry

et al. 2020

Nucleic Acids Research

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“…Rocaglates (including rocaglamide A, silvestrol, and other flavaglines) also suppress the activity of eIF4A, but their mechanism of action is less characterized (figure, i.5) [ 219 221]. Ribosome profiling revealed that eIF4A inhibition by some of these drugs causes a sequence specific arrest of the scanning ribosome at the 5′ untranslated region (see discussion in [221]). In the latest study, rocaglates were found to act in a dual fashion: first, they disturb the landing of eIF4F and the initiator complex on the 5′ cap and then inhibit the ribosomal scanning [221].…”

Section: Inhibitors Of Eukaryotic Translation Factorsmentioning

confidence: 99%

A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis

Dmitriev

Vladimirov

Lashkevich

2020

Biochemistry Moscow

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Eukaryotic ribosome and cap-dependent translation are attractive targets in the antitumor, antiviral, anti-inflammatory, and antiparasitic therapies. Currently, a broad array of small-molecule drugs is known that specifically inhibit protein synthesis in eukaryotic cells. Many of them are well-studied ribosome-targeting antibiotics that block translocation, the peptidyl transferase center or the polypeptide exit tunnel, modulate the binding of translation machinery components to the ribosome, and induce miscoding, premature termination or stop codon readthrough. Such inhibitors are widely used as anticancer, anthelmintic and antifungal agents in medicine, as well as fungicides in agriculture. Chemicals that affect the accuracy of stop codon recognition are promising drugs for the nonsense suppression therapy of hereditary diseases and restoration of tumor suppressor function in cancer cells. Other compounds inhibit aminoacyl-tRNA synthetases, translation factors, and components of translation-associated signaling pathways, including mTOR kinase. Some of them have antidepressant, immunosuppressive and geroprotective properties. Translation inhibitors are also used in research for gene expression analysis by ribosome profiling, as well as in cell culture techniques. In this article, we review well-studied and less known inhibitors of eukaryotic protein synthesis (with the exception of mitochondrial and plastid translation) classified by their targets and briefly describe the action mechanisms of these compounds. We also present a continuously updated database (http://eupsic.belozersky.msu.ru/) that currently contains information on 370 inhibitors of eukaryotic protein synthesis.

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“…Rocaglates and Pateamine A (and analogs) are interfacial inhibitors that cause eIF4A to clamp onto RNA, significantly stabilizing the resulting complex [164,165]. This gain-of-function produces a number of effects on translation initiation that inhibits the pathway through several modes: (i) clamped eIF4A molecules on 5 leader regions inhibit scanning, (ii) eIF4F becomes clamped at the cap resulting in a reduced 43S pre-initiation complex loading, and (iii) stabilization of eIF4F onto RNA diminishes the pool of eIF4F and exerts an effect in trans on initiation [166]. Furthermore, eIF4A appears to also become clamped to ribosomes, the functional consequence of which remains to be investigated [167].…”

Section: Targeting Ddx/dhx-box Helicases In Translation Initiationmentioning

confidence: 99%

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

Shen

Pelletier

2020

IJMS

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DExD (DDX)- and DExH (DHX)-box RNA helicases, named after their Asp-Glu-x-Asp/His motifs, are integral to almost all RNA metabolic processes in eukaryotic cells. They play myriad roles in processes ranging from transcription and mRNA-protein complex remodeling, to RNA decay and translation. This last facet, translation, is an intricate process that involves DDX/DHX helicases and presents a regulatory node that is highly targetable. Studies aimed at better understanding this family of conserved proteins have revealed insights into their structures, catalytic mechanisms, and biological roles. They have also led to the development of chemical modulators that seek to exploit their essential roles in diseases. Herein, we review the most recent insights on several general and target-specific DDX/DHX helicases in eukaryotic translation initiation.

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Rocaglates Induce Gain-of-Function Alterations to eIF4A and eIF4F

Abstract: Highlights d Rocaglates produce distinct inhibitory effects on translation initiation d Rocaglates interfere with eIF4F release from the cap structure d Rocaglates exert a bystander effect on translation initiation by sequestering eIF4F

Cited by 52 publications

References 20 publications

Identification and characterization of hippuristanol-resistant mutants reveals eIF4A1 dependencies within mRNA 5′ leader regions

Identification and characterization of hippuristanol-resistant mutants reveals eIF4A1 dependencies within mRNA 5′ leader regions

A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

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