SARS-CoV-2 protein NSP2 enhances microRNA-mediated translational repression

Naeli, Parisa; Snell, Patric Harris; Chatterjee, Susanta; Kamran, Muhammad; Ladak, Reese Jalal; Orr, Nick; Sonenberg, Nahum; Jafarnejad, Seyed Mehdi

doi:10.1101/2023.01.01.522328

Cited by 2 publications

(2 citation statements)

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“…An alternative mechanism has been reported for Sendai virus, where it boosts the production of the host interferon-stimulated genes ISG56 and ISGP54, which in turn inhibit translation initiation through binding to eIF3C and eIF3E, antagonizing eIF2-GTP-Met-tRNAi loading, and preventing the PIC recruitment to eIF3 (Guo et al, 2000; Hui et al, 2003; Terenzi et al, 2006). We previously reported that the SARS-CoV-2 derived NSP2 protein represses translation of Ifnb1 (Xu et al, 2022) and other mRNAs (Naeli et al, 2023b) through co-opting the GIGYF2/4EHP complex. However, NSP2 does not interact with GIGYF1 (Davies et al, 2020; Gordon et al, 2020; Xu et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Repression of mRNA translation initiation by GIGYF1 via blocking the eIF3-eIF4G1 interaction

Choi,

Luo,

Hesketh

et al. 2023

Preprint

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Viruses commonly interfere with the function of the eukaryotic translation initiation factor 4G1 (eIF4G1), a pivotal factor in the recruitment of the eIF3 complex and ribosome to the mRNA. This results in the inhibition of general host protein synthesis and redirecting ribosomes toward viral mRNAs. Certain viruses also selectively repress the translation of mRNAs involved in the host antiviral response. GIGYF2 and its interacting cap-binding protein 4EHP enable the transcript-specific repression of mRNA translation mediated by microRNAs and RNA-binding proteins (RBPs). RNA viruses, such as SARS-CoV-2, exploit the GIGYF2/4EHP complex to selectively repress the translation of transcripts such as Ifnb1 mRNA, which encodes the antiviral cytokine Interferon β (IFN-β). Herein, we reveal that GIGYF1, a paralogue of GIGYF2, robustly represses cellular mRNA translation through a distinct mechanism independent of 4EHP. Upon recruitment to a target mRNA by RBPs, the C-terminal region of GIGYF1 binds to subunits of eIF3 at the interaction interface of eIF3-eIF4G1. This disrupts the recruitment of eIF3 to the mRNA by eIF4G1, resulting in mRNA-specific translational repression. This mechanism exerts profound influences on the host cell's response to viral infection. Depletion of GIGYF1 induces a robust immune response by derepressing Ifnb1 mRNA translation. Overall, our study highlights a unique mechanism of translational regulation by GIGYF1 that involves sequestering eIF3 and abrogating its binding to eIF4G1. This mechanism can be utilized by RBPs that interact with GIGYF1 to specifically repress the translation of their target mRNAs, significantly affecting critical biological processes, including host-pathogen interactions.

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Section: Discussionmentioning

confidence: 99%

Repression of mRNA translation initiation by GIGYF1 via blocking the eIF3-eIF4G1 interaction

Choi,

Luo,

Hesketh

et al. 2023

Preprint

Self Cite

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“…4EHP and GIGYF2 mediate the translational repression of mRNAs targeted by microRNAs [ 69 - 71 ]. NSP2 enhances the microRNA-induced translational silencing through interaction with GIGYF2 and stabilisation of the GIGYF2/4EHP complex [ 76 , 77 ]. Once thought to be exclusively a host-related mechanism, microRNAs are also expressed by viruses to control both host and viral gene expression [ 78 ].…”

Section: Mechanisms Of Evasion Of Ifn Production By Sars-cov-2mentioning

confidence: 99%

Mechanisms of impairment of interferon production by SARS-CoV-2

Hoang

Naeli

Alain

et al. 2023

Biochemical Society Transactions

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Interferons (IFNs) are crucial components of the cellular innate immune response to viral infections. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a remarkable capacity to suppress the host IFN production to benefit viral replication and spread. Thus far, of the 28 known virus-encoded proteins, 16 have been found to impair the host's innate immune system at various levels ranging from detection and signaling to transcriptional and post-transcriptional regulation of expression of the components of the cellular antiviral response. Additionally, there is evidence that the viral genome encodes non-protein-coding microRNA-like elements that could also target IFN-stimulated genes. In this brief review, we summarise the current state of knowledge regarding the factors and mechanisms by which SARS-CoV-2 impairs the production of IFNs and thereby dampens the host's innate antiviral immune response.

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SARS-CoV-2 protein NSP2 enhances microRNA-mediated translational repression

Cited by 2 publications

References 61 publications

Repression of mRNA translation initiation by GIGYF1 via blocking the eIF3-eIF4G1 interaction

Repression of mRNA translation initiation by GIGYF1 via blocking the eIF3-eIF4G1 interaction

Mechanisms of impairment of interferon production by SARS-CoV-2

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