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Targeting eEF1A reprograms cellular translation and uncovers alternative broad-spectrum antivirals against cap or m6A protein synthesis routes

ABSTRACT: Targeting eEF1A reprograms cellular translation and uncovers alternative broad-spectrum antivirals against cap or m6A protein synthesis routes

PROVIDER: PRJNA1126260 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29481925_1.fastq.gz	Fastqsanger.gz
	SRR29481925_2.fastq.gz	Fastqsanger.gz
	SRR29481926_1.fastq.gz	Fastqsanger.gz
	SRR29481926_2.fastq.gz	Fastqsanger.gz
	SRR29481927_1.fastq.gz	Fastqsanger.gz

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Targeting eEF1A reprograms cellular translation and uncovers alternative broad-spectrum antivirals against cap or m6A protein synthesis routes

Project description:Plitidepsin is an antitumoral drug safe for treating COVID-19 infection that impairs SARS-CoV-2 replication by targeting the translation elongation factor eEF1A. Here we show that plitidepsin decreased all SARS-CoV-2 transcripts along the early translation of viral R1AB polyproteins and the late synthesis of structural viral proteins. It also reduced de novo cap-dependent translation of viral and non-viral RNAs but affected less than 13% of the host proteome, thus preserving cellular viability. In response to plitidepsin, cells upregulated EIF2AK3 and additional proteins that reduce translation. Other proteins supported proteostasis via ribosome synthesis and cap-independent translation routes, which relied on eIF4G2, PABPC1, and readers such as IGF2BP2. While cap- or internal ribosome entry sites (IRES)-mediated translation pathways were inhibited by plitidepsin, impact on N6-methyladenosine (m6A) translation was limited. The molecular landscape reprogrammed by cells treated with plitidepsin predicted a potential broad-spectrum activity against viruses translated via cap- or IRES-dependent pathways that were suppressed by m6A. In agreement, plitidepsin inhibited the replication of members from the Coronaviridae, Flaviviridae, Pneumoviridae and Herpesviridae families. Yet, it failed to block retroviruses that exploit m6A synthesis routes and are inhibited by drugs against specific m6A readers such as IGF2BP2. By deciphering the molecular fingerprint of cells treated with host-directed therapies targeting protein translation, we identified a rational approach to select for broad-spectrum antivirals with complementary activities and potential to counteract future pandemic viruses.

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Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m<sup>6</sup>A protein synthesis routes.

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Expression data from Saccharomyces cerevisiae with eEF1A overexpression

Project description:The canonical role of eEF1A is to deliver the aminoacyl tRNA to the ribosome, we have used the yeast model system to investigate further roles for this protein. We used microarray to study the transcriptomic effects of elevated levels of eEF1A on yeast cells during log phase growth

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Project description:Cotranslational protein folding depends on general chaperones that engage highly diverse nascent chains at the ribosomes. Here we find that the universal cotranslational machinery adapts to accommodate the challenging biogenesis of abundantly expressed eukaryotic translation elongation factor 1A (eEF1A). During eEF1A synthesis, chaperone Chp1 is recruited to the ribosome with the help of the nascent polypeptide-associated complex (NAC), where it safeguards eEF1A biogenesis. Aberrant eEF1A production triggers instant proteolysis, widespread protein aggregation, activation of Hsf1 stress transcription and compromises cellular fitness. The expression of pathogenic eEF1A2 variants linked to epileptic-dyskinetic encephalopathy is protected by Chp1. Thus, eEF1A is a difficult to fold protein that necessitates dedicated folding factor Chp1 at the ribosomal tunnel exit to protect the eukaryotic cell from proteostasis collapse.

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