Study shows SARS-CoV-2 impairs interferon production through NSP2-induced repression of mRNA translation

In a recent study published in PNAS, researchers discovered a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structural protein 2 (NSP2)-mediated mechanism by which it suppresses the production of interferon-beta (IFN-β) in host cells.

Study: SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation. Image Credit: CROCOTHERY/Shutterstock


Studies have demonstrated the crucial role of type I IFNs in combating viral infections. A robust IFN-induced antiviral response limits SARS-CoV-2 replication in the early phase of infection and prevents progrssion to severe coronavirus disease 2019 (COVID-19).

Multiple SARS-CoV-2 proteins, including NSPs and open reading frame (ORF) proteins, potently inhibit IFN-β1 transcription. Likewise, studies have reported that the production of type I IFNs is controlled at messenger ribonucleic acid (mRNA) translational levels during SARS-CoV-2 infection. However, studies have not reported specific repression of IFN-β1 mRNA translational machinery to support the translation of SARS-CoV-2 mRNA.

About the study

In the present study, researchers reported a novel mechanism by which the SARS-CoV-2 NSP2 designates the Grb10-interacting glycine, tyrosine, phenylalanine protein 2 ( GIGYF2)/ eIF4E‐homologous protein (4EHP) translational repressor complex to impede IFN-β1 mRNA expression, resulting in enhanced SARS-CoV-2 replication and subsequent evasion of an antiviral cellular innate immune response.

Several large-scale proteomic studies have reported the interaction of SARS-CoV-2 NSP2 with 4EHP and GIGYF2. The researchers used proximity ligation assay (PLA) to visualize the interaction of NSP2 with the GIGYF2/4EHP complex in HEK293T cells transfected with vectors expressing v5-tagged GIGYF2, 4EHP, or GIGYF1 and FLAG-NSP2. They counted PLA signals from at least 30 cells in each sample, presented as mean ± standard deviation (SD). Next, the team mapped the region of GIGYF2 responsible for binding NSP2. They used coimmunoprecipitation (co-IP) experiments to study these interactions.

Further, the researchers used a green fluorescent protein (GFP)-tagged mutant strain of vesicular stomatitis virus (VSVΔ51) to study how GIGYF2 repressed IFN-β production. The mutant had no methionine-51 (M51) in the matrix protein, which rendered it more sensitive to the IFN antiviral activity. The team measured the expression of IFN-β in A549 lung cells infected with GFP-tagged VSVΔ51 using an enzyme-linked immunosorbent assay [ELISA]. Additionally, they used reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to measure the mRNA level of the IFN-stimulated gene 56 (ISG56) in A549 lung cells following VSVΔ51 infection.

Study findings

PLA detected sites of NSP2–GIGYF2 interactions as fluorescent punctate in HEK293T cells. PLA also detected interaction of NSP2 with full-length (FL) GIGYF2 and fragment E (742–1,085) and with the partially overlapping GIGYF2 and fragment D (621–752).

Similar to PLA results, co-IP results showed that GIGYF2 and 4EHP coprecipitated with FLAG- NSP2. IP assays also showed a slight but significant increase in binding of NSP2 to fragment E compared to the FL GIGYF2, likely due to slight increase in expression of fragment E compared with the FL GIGYF2 as demonstrated via Western blots. Together, the study data showed that the NSP2-interacting region of GIGYF2 spanned residues 742–1,085, i.e., fragment E. Further narrowing revealed that the GIGYF2 region spanning amino acids 860–919 interacted with NSP2 and AlphaFold 2 predicted that the long-alpha helix region (LHR) between amino acid residues 723 and 919 encapsulated this GIGYF2 region.

Compared to wild-type (WT) cells, expression of IFN-β and the mRNA level of ISG56 increased approximately two-fold in A549 cells without a detectable change in IFN-β1 mRNA levels. The GIGYF2-depletion protected these cells from mutant viral infection due to vigorous IFN-β production and activating IFN-induced antiviral pathways. At least two different RNA viruses likely use distinct ways that end up on the GIGYF2/4EHP translational repression complex to block the activation of the antiviral innate immune response.

Another recent study also showed that SARS-CoV-2 expresses microRNAs (miRNA) that selectively repress host genes associated with IFN signaling. This raises the possibility that SARS-CoV-2 encoded NSP2 could also designate the GIGYF2/4EHP complex to enhance the repression of the cellular targets of the viral coded miRNAs.


The study findings discovered a molecular mechanism that could rescue the innate immune response to SARS-CoV-2 and other RNA viruses. The knowledge of the three-dimensional structure of the LHR of GIGYF2 and its interaction with the NSP2 binding region could be invaluable for better understanding the molecular mechanisms governing the study identified NSP2/GIGYF2/4EHP complex. Additionally, it could inform the development of small peptides to block the NSP2-GIGYF2 interaction for combating future SARS-CoV-2 infections and other coronaviruses.

Journal reference:
  • Zhang Xu, Jung-Hyun Choi, David L. Dai, Jun Luo, Reese Jalal Ladak, Qian Li, Yimeng Wang, Christine Zhang, Shane Wiebe, Alex C. H. Liu, Xiaozhuo Ran, Jiaqi Yang, Parisa Naeli, Aitor Garzia, Lele Zhou, Niaz Mahmood, Qiyun Deng, Mohamed Elaish, Rongtuan Lin, Lara K. Mahal, Tom C. Hobman, Jerry Pelletier, Tommy Alain, Silvia M. Vidal, Thomas Duchaine, Mohammad T. Mazhab-Jafari, Xiaojuan Mao, Seyed Mehdi Jafarnejad, Nahum Sonenberg. (2022). SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation. PNAS. doi:

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Amino Acid, Assay, Coronavirus, Coronavirus Disease COVID-19, covid-19, ELISA, Enzyme, Fluorescent Protein, Gene, Genes, Glycine, Helix, Homologous, Immune Response, Interferon, Ligation, Methionine, Peptides, Phenylalanine, Polymerase, Polymerase Chain Reaction, Protein, Respiratory, Ribonucleic Acid, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Stomatitis, Structural Protein, Syndrome, Transcription, Translation, Tyrosine, Virus

Comments (0)

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

Source: Read Full Article