COVID-19 News: SARS-CoV-NSP2 Protein Enhances microRNA-Mediated Translational Repression With Serious Long Term Health Implications!

COVID-19 News: A new study by researchers from Queen’s University Belfast, Belfast, UK has discovered that the SARS-CoV-2 encoded non-structural protein 2 (NSP2) enhances microRNA-mediated translational repression.


 
It is already known that most viruses utilize miRNAs to impair the host antiviral immune system and facilitate viral infection by expressing their own miRNAs or co-opting cellular miRNAs.
 
It was earlier reported that the SARS-CoV-2 NSP2 protein also interacts with GIGYF2 was covered in our previous COVID-19 News article.
 
https://www.thailandmedical.news/news/breaking-hypothesis-that-majority-exposed-to-sars-cov-2-will-have-shortened-lifespans-validated-by-study-showing-nsp2-impairs-human-4ehp-gigyf2-comple
 
Viruses deploy such a strategy for blocking translation of the Ifn1-b mRNA that encodes the cytokine Interferon-ß, and thereby impairs the host antiviral immune response.
 
However, to date it is not clear as whether NSP2 also affects miRNA-mediated silencing.
 
However, the study findings showed the pervasive augmentation of the miRNA-mediated translational repression of cellular mRNAs by NSP2. It was found that NSP2 interacts with Argonaute 2, the core component of the miRNA-Induced Silencing Complex (miRISC) and enhances the translational repression mediated by natural miRNA binding sites in the 3´ UTR of cellular mRNAs.
 
These findings reveal an additional layer of the complex mechanism by which SARS-CoV-2 and likely other coronaviruses manipulate the host gene expression program through co-opting the host miRNA-mediated silencing machinery.
 
In essence, the SARS-CoV-2 NSP2 protein is able to stop the GIGYF2 and 4EHP from inhibiting translation initiation of defective messenger RNAs and genes that typically assist ribosome-associated quality control!
 
The dangerous repercussions from the impairment of such an important cellular process is varied and the inability to block translation of faulty mRNAs and subsequent accumulation of partially synthesized polypeptides could lead to many health disorders ranging from neurodevelopmental and neuropsychiatric disorders, heart disorders, immune issues, cancers and a host of health issues which shortens a person’s lifespan!
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2023.01.01.522328v1
 
Typically, microRNAs (miRNA) are small, ∼22 nucleotides long, non-coding RNAs that modulate the stability and translation efficiency of their target mRNAs. This is mediated by miRNA-Induced Silencing Complex (miRISC), an assembly of a miRNA, Argonaute (AGO), and other proteins, in which miRNA guides the complex to the target mRNA by sequence complementarity. Thi s leads to translational repression followed by deadenylation and decapping of the mRNA, resulting in the exposure of the mRNA to exonuclease-mediated degradation.
 
The CCR4- NOT complex plays a key role in coordinating the intricate mechanism of regulation of mRNA translation and decay induced by miRNAs. While miRNA-mediated deadenylation is achieved by the activity of the components of the catalytic subunits of the CCR4-NOT complex (CNOT6/6L and CNOT, translational repression and decapping are engendered through recruitment of several CCR4-NOT binding proteins.
 
The study team previously discovered that recruitment of the mRNA cap-binding eIF4E-homologue protein (4EHP), by CCR4–NOT is critical for the miRNA-mediated translational repression of target mRNAs.
https://www.pnas.org/doi/full/10.1073/pnas.1701488114
 
The 4EHP also forms a translational repressor complex with Grb10-interacting GYF protein 2 (GIGYF2), which represses mRNA translation in CCR4-NOT dependent and independent manners.
 
The GIGYF2/4EHP complex is recruited by a variety of factors including miRNAs, the RNA binding protein Tristetraprolin (TTP), and the stalled ribosome induced Ribosome-associated Quality Control (RQC) mechanism via ZNF598 or EDF1 to repress translation.
 
Most viruses typically use a variety of mechanisms to modulate host gene expression. A common strategy adopted by viruses involves the general shut down of the host mRNAs translation, which allows redirecting the host's ribosomes toward the viral mRNAs to express the viral proteins.
https://pubmed.ncbi.nlm.nih.gov/32757266/
 
Some of these mechanisms include:
 
-blocking the cap-dependent translation initiation via sequestering
 
-cleavage of the eukaryotic Initiation factor 4G (eIF4G),
 
-binding to and inducing the inhibition or degradation of the poly(A)-binding protein (PABP)
 
-binding to the components of the eIF3 complex.
 
Most RNA viruses bypass the need for cap-dependent translation initiation by utilizing an internal ribosome entry site (IRES) in the viral mRNA’s 5′ UTRs to enable translation in a “cap-independent” manner.
 
Besides shutdown of general cap-dependent translation, viruses also employ “targeted” impairment of the host cell’s homeostasis and proinflammatory responses by changing the expression of miRNAs that target specific host mRNAs.
https://pubmed.ncbi.nlm.nih.gov/22787204/
 
https://europepmc.org/article/med/33581076
 
Interestingly, certain viruses express their own miRNAs that target cellular mRNAs.
https://pubmed.ncbi.nlm.nih.gov/34903581/
 
The study findings provide evidence of a pervasive effect of NSP2 on miRNA-mediated silencing and shows that besidesGIGYF2, NSP2 also interacts with the components of miRISC complex and enhances the translational repression of their target mRNAs.
 
The study team previously showed that NSP2 facilitates SARS-CoV-2 viral replication by augmenting GIGYF2/4EHP-mediated repression of Ifnb1 mRNA, which encodes the key cytokine IFNß.
 
Importantly, Ifnb1 mRNA contains the binding sites for multiple miRNAs including let-7, miR-34a, miR-26a, and miR-145.
 
Computational analyses identified a substantial number of potential miRNAs encoded by the SARS-CoV-2 genome, many of which were predicted to target mRNAs that encode proteins with important roles in immune-regulatory processes such as NF-κB, JAK/STAT, and TGFß signaling pathways.
https://pubmed.ncbi.nlm.nih.gov/33398248/
 
However, subsequent studies empirically identified multiple miRNAs derived from the viral genome, which impaired the host antiviral response by targeting the 3´ UTR of various mRNAs that encode IRF7, IRF9, STAT2, and interferon stimulated genes (e.g. ISG15, MX1, and BATF2).
https://pubmed.ncbi.nlm.nih.gov/35003084/
 
https://pubmed.ncbi.nlm.nih.gov/34903581/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8811647/
 
https://pubmed.ncbi.nlm.nih.gov/28216251/
 
hence, it is thus likely that enhanced translational repression of targets of both viral and host miRNA through the function of NSP2 serves to impair a host innate immune response against SARS-CoV-2 infection.
 
In principle NSP2 could also enhance the silencing mediated by antiviral miRNAs.
 
In order to avoid the potential harmful effects of NSP2-induced repression by antiviral miRNAs, the virus can manipulate the expression pattern of antiviral miRNAs.
https://www.frontiersin.org/articles/10.3389/fimmu.2022.1008084/full
 
https://pubmed.ncbi.nlm.nih.gov/33651636/
 
https://www.medrxiv.org/content/10.1101/2020.06.16.20133256v1
 
https://pubmed.ncbi.nlm.nih.gov/34564316/
 
https://pubmed.ncbi.nlm.nih.gov/32858958/
 
Analysis of the expression of 128 human miRNAs with potential to target the SARS-CoV-2 genome revealed their very low expression in lung epithelia, which likely allows the virus to avoid the effects of antiviral miRNAs and replicate in these cells.
 
It is estimated that miRNAs target over 60% of human protein-coding mRNAs and affect important processes including development, cell proliferation, metabolism, and maintenance of homeostasis.
https://pubmed.ncbi.nlm.nih.gov/25484347/
 
Dysregulated miRNA expression and activity has been linked to diseases including cancer and metabolic disorders.
https://pubmed.ncbi.nlm.nih.gov/20466882/
 
https://pubmed.ncbi.nlm.nih.gov/30364956/
 
Thus, control of miRNA-mediated translational repression by NSP2 during SARS-CoV-2 infection could have significant pathophysiological impacts. Importantly, NSP2, or NSP2-derived peptides that preserve the ability to augment the GIGYF2/4EHP complex could potentially be used to modulate miRNA mediated silencing, independent of SARS-CoV-2 infection.
 
For example, global miRNA expression is often downregulated in cancers, due to various reasons such as dysregulated expression of miRNA biogenesis factor Dicer.
https://pubmed.ncbi.nlm.nih.gov/25783160/
 
https://pubmed.ncbi.nlm.nih.gov/22689055/
 
https://pubmed.ncbi.nlm.nih.gov/25052766/
 
https://pubmed.ncbi.nlm.nih.gov/19092150/
 
Though in the transcriptome-wide scale each miRNA can potentially target hundreds of mRNAs, miRNAs generally have relatively subtle impacts on the stability or translation of individual target mRNAs.
 
Furthermore, the miRNA-mediated silencing machinery has a limited capacity and is prone to saturation. This limited capacity for miRNA-mediated silencing machinery should be considered when interpreting data generated by transfection of ectopic miRNAs, reporter mRNAs with miRNA-binding sites, or when tethering components of miRISC.
 
It should be noted that in addition to mediating the miRNA-induced repression of the cap-dependent mRNA translation, the GIGYF2/4EHP complex can also take part in silencing of target mRNAs triggered by ribosome stalling (Ribosome-associated Quality Control; RQC) or RNAbinding proteins such as Tristetraprolin or TTP.
 
Tristetraprolin (TTP) and its paralogues ZFP36L1 and ZFP36L2 have significant roles in cancer and regulation of the immune system through binding and repressing the expression of mRNAs that contain the A/U rich element.
https://pubmed.ncbi.nlm.nih.gov/24840979/
 
Importantly, a recent study also revealed the biological importance of RQC in neurological disorders.
https://pubmed.ncbi.nlm.nih.gov/36187485/
 
It has to be understood that these study findings alarmingly show how the SARS-CoV-2 virus is able to cause serious cellular damage by affecting these important gene regulatory processes and can literally shorten the life spans of those infected!
 
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