BREAKING! Hypothesis That Majority Exposed To SARS-CoV-2 Will Have Shortened Lifespans Validated By Study Showing NSP2 Impairs Human 4EHP-GIGYF2 Complex!

Since late March 2022, Thailand Medical News has been proposing our hypothesis that majority of individuals who have been exposed to the SARS-CoV-2 virus, irrespective of the initial conditions upon infection ie asymptomatic or mild to severely symptomatic, will have their lifespans reduced. https://www.thailandmedical.news/news/most-who-have-been-exposed-to-the-proteins-of-the-sars-cov-2-virus-will-have-shortened-lifespans-stop-using-fluvoxamine-for-ba-2-infections



Based on our own analysis of the 283 of the 347 known cellular pathways and various genes that are either disrupted, damaged or made dysfunctional by the SARS-CoV-2 coronavirus and its various viral proteins, we postulate on an optimistic perspective that a majority of the exposed population will only have between 5 to 8 years left. However, constant reinfections and also exposure to newer variants with newer pathogenic modes can make conditions worse and also further shorten these remaining lifespans.
Read Also: https://www.thailandmedical.news/news/breaking-italian-study-validates-previous-claims-that-sars-cov-2-infections-causes-immunodeficiency-conditions-worse-than-hiv-infections
 
A new study by researchers in the field of molecular biology, genetics and oncology from the Laboratoire de Biologie Structurale de la Cellule (BIOC), CNRS, Ecole Polytechnique- France has found that the NSP2 proteins of the SARS-CoV-2 coronavirus is able to bind to the human 4EHP-GIGYF2 complex, impairing microRNA-mediated silencing!
 
This basically means that the SARS-CoV-2 NSP2 protein basically stops the GIGYF2 and 4EHP from inhibiting translation initiation of defective messenger RNAs and genes that typically assist ribosome-associated quality control!
 
The study team focused their attention on the capacity of the SARS-CoV-2 protein NSP2 to bind the human 4EHP-GIGYF2 complex, a key factor involved in microRNA-mediated silencing of gene expression.
 
Utilizing in vitro interaction assays, the study findings demonstrate that NSP2 physically associates with both 4EHP and a central segment in GIGYF2 in the cytoplasm.
 
The study findings also provide functional evidence showing that NSP2 impairs the function of GIGYF2 in mediating translation repression using reporter-based assays.
 
The study findings alarmingly reveal the potential impact of NSP2 on the post-transcriptional silencing of gene expression in human cells, pointing out 4EHP-GIGYF2 targeting as a possible strategy of SARS-CoV-2 to take over the silencing machinery and to suppress host defenses.
 
The study findings were published in the peer reviewed journal: i Science by Cell Press. https://www.cell.com/iscience/fulltext/S2589-0042(22)00918-X
 
The repercussions from the impairment of such an important cellular process is varied and the inab ility 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 shorten a person’s lifespan.
https://www.sciencedirect.com/science/article/pii/S1097276520304731
 
https://www.frontiersin.org/articles/10.3389/fgene.2018.00431/full
 
https://molecularautism.biomedcentral.com/articles/10.1186/s13229-020-00394-7
 
Hence this new study also adds to the growing evidence and validation of our hypothesis that all those who got exposed to the SARS-CoV-2 virus would have shortened lifespans. Kindy note that the possible extend of health damage that impairment of the function of GIGYF2 in mediating translation of defective mRNAs that is covered here is just a small fraction of the short-term and mid -term damage that can occur. We suggest that readers delve further to explore and truly understand the consequences of human 4EHP-GIGYF2 complex impairment.
 
Most people are not even aware that their bodies are gradually failing as a result of the exposure to the SARS-CoV-2 virus and will either only realize it when it is too late and a major condition develops or unless they are lucky enough and simply meet with a fast deadly outcome like a heart failure or a lethal stroke!
 
The study findings showed that SARS-CoV-2 NSP2 directly targets the 4EHP-GIGYF2 complex to decrease its silencing capacity.
 
There is a strong possibility that the virus is using this strategy to downregulate certain immune responses and also immune genes.
 
The study findings showed that NSP2 uses its N-terminal region encompassing its conserved zinc finger domain, to interact with the 4EHP-GIGYF2 complex.
 
The pull-down assays indicate the direct interaction of NSP2 with both 4EHP and two domains from GIGYF2, confirming a sophisticated mode of binding in cellulo.
 
The G262V and G265V mutations located within this region of NSP2 reduced binding to 4EHP-GIGYF2. This natural variation occurs in a poorly conserved patch in NSP2 that is subsequently becoming more hydrophobic due to the G to V substitution.
 
The study team said that It is worth noting that G262 and G265 are not conserved across the SARS-CoV-1 and MERS-CoV viruses.
 
Measurement of miRNA action showed that translational repression accounts for 6–26% of the silencing of each mRNA target in mammalian cells, and 4EHP-GIGYF2-mediated translational repression is observed at early time points of the silencing process.
 
Consistent with these observations, the impact of NSP2 remains mild on the let7a-targeted RLuc reporter. The latter is also known to underestimate the contribution of the translational repression to the silencing process since mRNA destabilization is the dominant effect of miRNA-mediated silencing at steady state.


 
The team’s tethering assays with GW182SD have proven helpful to overcome this limitation. The derepression of the GW182SD-induced silencing of RLuc-5BoxB-A114-N40-HhR upon deletion of the PPGL motif supports the fact that their tethering assay faithfully recapitulates the contribution of GIGYF2 into miRNA-induced translation repression. Consistently, these tethering assays showed that the silencing capacity of GW182SD upon NSP2 expression equals the one of its ΔPPGL version in control cells, indicating that the contribution of 4EHP-GIGYF2 into GW182SD-mediated translation repression is fully targeted by NSP2. Indeed, this impact of NSP2 will need to be investigated in further more physiological studies using endogenous miRNAs and transcripts. 
 
Currently, it is uncertain what the functional interplay between SARS-CoV-2 infection and miRNA-mediated silencing is in human cells. Host miRNAs are known to be produced as a part of antiviral response to counteract the infection by targeting viral transcripts, although SARS-CoV-2 infection was recently shown to have minimal impact on the miRNA repertoire of its host cell.
 
Detailed computational analyses have predicted the presence of many putative miRNA-binding sites on the SARS-CoV-2 genome, suggesting that the SARS-CoV-2 genome could be actively targeted by host miRNAs.
 
A recent study identified let-7 binding sites in the coding sequence of S and M proteins of SARS-CoV-2 genome, and experimentally confirmed that let-7 blocks SARS-CoV-2 replication by targeting S and M proteins.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897876/
 
Through the NSP2/4EHP-GIGYF2 axis, SARS-CoV-2 could therefore escape from the host defense system by impairing the function of the effector machinery of miRNAs.
 
Although the silencing capacity of miRISC is partially impeded upon NSP2 expression, there is no guarantee that miRNA action is the prime target of NSP2. The activity of 4EHP-GIGYF2 is mobilized by several pathways, one of which may be more affected than miRNAs. These pathways include TTP- and ZNF598-mediated mRNA silencing, as well as the repression of mRNAs with altered ribosome activity or premature termination codons as part of the nonsense-mediated mRNA decay pathway.
 
In the case of miRNA, the alteration of let-7a-mediated inhibition by NSP2 could be extrapolated to other miRNAs whose action relies on 4EHP, such as miR-145 or miR-34a.
 
Studies have demonstrated that the 4EHP/miR-34a axis is required for the translational repression of mRNAs encoding IFN-β through targeting the 3’UTR of Ifnb1 mRNA https://www.cell.com/molecular-cell/fulltext/S1097-2765(21)00050-2
 
Besides miRNA, 4EHP-GIGYF2 also controls the production of TTP-targeted mRNAs that encode inflammatory cytokines such as TNF-α and IL-8. Hence, in this context, a possible consequence of NSP2 expression could be the overproduction of early response pro-inflammatory cytokines.
 
The study team in order to examine whether NSP2 could impact the function of 4EHP in regulating IFN-β expression, expressed NSP2 along with a reporter construct containing the 3′ UTR of Ifnb1 mRNA into HEK293T cells.
 
Remarkably, the reporter expression was repressed ∼2.9-fold in control cells, but only ∼1.6-fold in NSP2-expressing cells, indicating that NSP2 could potentially unbalance the production of IFN-β through the Ifnb1 3′ UTR.
 
The study team concluded that their findings shows that SARS-CoV-2 targets the human 4EHP-GIGYF2 complex to selectively modulate its capacity to effect translation repression.
 
With all the various studies indicating the various ways that the human host cellular pathways and genes are being disrupted, damaged and made dysfunctional by exposure to the SARS-CoV-2 virus, the various emerging conditions associated with Long COVID are nothing compared to what is in store for those that are still alive.
 
For more on SARS-CoV-2 and how it kills the human host slowly, keep on logging to Thailand Medical News if you are still able to!