S2 of SARS-2 spike buggers up p53

According to a recent study in preprint...

Please refer to the newly uploaded article entitled “SARS-CoV-2 spike S2 subunit inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells”.¹

The authors report that the S2 component of the spike protein interferes with p53 signaling in cancer cells. There’s a protein called MDM2 that acts in tandem with p53: MDM2 ubiquitinates (protein synthesis/degradation stuff) p53, and p53 activates transcription of MDM2. I scratch your back, you scratch mine. See spike S2 component below in Figure 1.²

Figure 1: Spike-protein-mediated membrane fusion. Esteban Dodero-Rojas Jose N Onuchic Paul Charles Whitford (2021). Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion eLife 10:e70362. https://doi.org/10.7554/eLife.70362 The authors write:

The bottom line here is that the component of the spike protein of SARS-2, S2, responsible for cell entry as part of receptor-mediated endocytosis, messes up p53 activity. We all know by now that p53 - the guardian of the genome - assures that double-stranded DNA breaks are repaired and genome mutations limited, by surveillance of DNA and control of the cell cycle.

The suppressive effect of SARS-CoV-2 spike on p53-dependent gene activation provides a potential molecular mechanism by which SARS-CoV-2 infection may impact tumorigenesis, tumor progression and chemotherapy sensitivity.

This is the same spike S2 that is indeed encoded in the template that was used in the COVID modified mRNA shots.

Figure 2: Spike protein production by human cells via LNP/modified mRNA transfection. https://www.genome.gov/about-genomics/fact-sheets/Understanding-COVID-19-mRNA-Vaccines - Courtesy: National Human Genome Research Institute

The authors aren’t sure yet how S2 is doing this, ie: is it interrupting “p53 binding to the DNA promoters of the targets”, is it “inhibiting p53 transcriptional activity through post-translational modifications in p53”, or is it “altering other proteins that complex with p53”. They rightly point out that we need to do more work to find out.

Once again, this is the kind of thing that should have been done prior to using the spike protein as the coding template for the COVID-19 shots that we all so desperately needed.

That’s all for now.

1. Shengliang Zhang, Wafik S. El-Deiry. SARS-CoV-2 spike S2 subunit inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells. bioRxiv 2024.04.12.589252; doi: https://doi.org/10.1101/2024.04.12.589252

2. Esteban Dodero-Rojas Jose N Onuchic Paul Charles Whitford. (2021) Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion. eLife 10:e70362. https://doi.org/10.7554/eLife.70362