Viral and cellular translation during SARS‐CoV‐2 infection

Eriani, Gilbert; Martin, Franck

doi:10.1002/2211-5463.13413

Cited by 16 publications

(9 citation statements)

References 112 publications

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“…Viruses have evolved diverse strategies that subvert host protein synthesis in order to downregulate host translation and optimize the translation of viral proteins (37)(38)(39)(40)(41). SARS-CoV-2 employs multiple mechanisms to disrupt host protein synthesis (12,(42)(43)(44)(45)(46)(47), and M pro -mediated cleavage of human TRMT1 could contribute to the modulation of cellular translation during viral infection. TRMT1 is a tRNA methyltransferase whose m2,2G26 modification activity directly impacts global translational efficiency.…”

Section: Discussionmentioning

confidence: 99%

Recognition and Cleavage of Human tRNA Methyltransferase TRMT1 by the SARS-CoV-2 Main Protease

D'Oliviera

Dai

Mottaghinia

et al. 2023

Preprint

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The SARS-CoV-2 main protease (Mpro) plays a crucial role in the production of functional viral proteins during infection and, like many viral proteases, can also target and cleave host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 can be recognized and cleaved by SARS-CoV-2 Mpro. TRMT1 installs the N2,N2-dimethylguanosine (m2,2G) modification at the G26 position of mammalian tRNA, which promotes global protein synthesis, cellular redox homeostasis, and has links to neurological disability. We find that Mpro can cleave endogenous TRMT1 in human cell lysate, resulting in removal of the TRMT1 zinc finger domain that is required for tRNA modification activity in cells. Evolutionary analysis shows that the TRMT1 cleavage site is highly conserved in mammals, except in Muroidea, where TRMT1 may be resistant to cleavage. In primates, regions outside of the cleavage site with rapid evolution could indicate possible adaptation to ancient viral pathogens. To visualize how Mpro recognizes the TRMT1 cleavage sequence, we determined the structure of a TRMT1 peptide in complex with Mpro, which reveals a substrate binding conformation distinct from the majority of available SARS-CoV-2 Mpro-peptide complexes. Kinetic parameters for peptide cleavage showed that while TRMT1(526-536) is cleaved much slower than the Mpro nsp4/5 autoprocessing sequence, it is proteolyzed with comparable efficiency to the Mpro-targeted nsp8/9 viral cleavage site. Mutagenesis studies and molecular dynamics simulations together indicate that kinetic discrimination occurs during a later step of Mpro-mediated proteolysis that follows substrate binding. Our results provide new information about the structural basis for Mpro substrate recognition and cleavage that could help inform future therapeutic design and raise the possibility that proteolysis of human TRMT1 during SARS-CoV-2 infection may impact protein translation or oxidative stress response and contribute to viral pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Recognition and Cleavage of Human tRNA Methyltransferase TRMT1 by the SARS-CoV-2 Main Protease

D'Oliviera

Dai

Mottaghinia

et al. 2023

Preprint

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“…For instance, DTU of IFI27 was observed in Basal Alpha (adult), Ciliated Alpha (adult & child), Cycling-basal Alpha (adult & child), Goblet Alpha (adult), Secretory Alpha (adult & child), Suprabasal Alpha (adult) datasets. Similarly, host ribosomes are manipulated by SARS-CoV-2 for viral protein translation (Eriani & Martin, 2022). We observed ribosomal genes such as RPL4 (Basal WT (child), Ciliated Alpha (adult), Goblet Alpha (child), Secretory Alpha (adult), Suprabasal Alpha (adult), Suprabasal WT (child)) and RPL15 (Basal Alpha (adult & child), Basal WT (child), Ciliated Alpha (adult & child), Ciliated WT (child), Cycling-basal Alpha (child), Cycling-basal WT (child), Goblet Alpha (child), Secretory Alpha (child), Secretory WT (child), Suprabasal Alpha (child), Suprabasal WT (child)) as being commonly DTU.…”

Section: Resultsmentioning

confidence: 99%

Uncovering strain- and age-dependent differences in innate immune response to SARS-CoV-2 infection in nasal epithelia using 10X single-cell sequencing

Chang

Grimley

Tran

et al. 2023

Preprint

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Assessing the impact of SARS-CoV-2 variants on host immune systems is crucial with the continuous arrival of novel variants. However, there is a lack of reported studies utilizing single-cell RNA-sequencing (scRNA-seq) to elucidate the age-dependent host-viral interactions with different SARS-CoV-2 strains. Therefore, we employed Full-Length Transcriptome Sequencing (FLT-Seq) combining Illumina and Oxford Nanopore Technologies (ONT) with 10X 3’ single cell sequencing to investigate host transcriptomic changes during wild-type (WT) and Alpha-strain SARS-CoV-2 infections within air-liquid-interface (ALI)-cultured human nasal epithelial cells from adults and adolescents. The results revealed increased innate immune responses in cells with lower viral loads which were lacking in cells with higher viral load. Alpha-infections showed heightened expression of genes related to interferon (IFN)-responses and protein-folding compared with WT, implying the increased immune response and endoplasmic reticulum stress with the variant of a higher transmission rate.ACE2expression was elevated in infected populations of secretory and goblet cells with high IFN-stimulation and a subpopulation of ciliated cells but was lacking in bystander cells and other infected-cell types, despite detectable IFN-stimulation and regardless of strain. We used long-read sequencing to identify differential transcript usage (DTU) of IFN-response and translational genes, includingIFI27,RPL4andRPL15(padj < 0.05) in infected cells compared with control, and consistent DTU ofRPL15andMX1between Alpha and WT strain-infected cells in various cell-types. Together, these results reveal the dynamic transcriptional/translational/post-translational activity upon SARS-CoV-2 infection, which appeared to be age and strain-dependent. Overall, this study highlights the complexity of cell-type, age and viral-strain-dependent host epithelial responses to SARS-CoV-2.

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“…Our third special issue of the year placed the limelight firmly on one specific virus: SARS‐CoV‐2. Guest editor Alexander Wlodawer commissioned three Review articles focussing on the structures of different proteins of SARS‐CoV‐2: Robin Stanley and co‐authors discussed the structure and function of ribonucleases [ 10 ]; Franck Martin and colleagues focussed on viral and cellular translation during SARS‐CoV‐2 infection, as mediated by NSP1 [ 11 ]; and finally, Xinquan Wang, Jiwan Ge and co‐authors discussed the evolution of and therapeutic targeting of the spike glycoprotein [ 12 ].…”

Section: New Developments In 2022mentioning

confidence: 99%