The SARS-CoV-2 spike protein, a class I viral fusion protein, is critical to initiating the interactions between the virus and the host cell surface receptor, facilitating viral entry into the host cell by assisting in the fusion of the viral and host cell membranes. This protein consists of two subunits: Subunit 1 (S1) that contains the ACE2 receptor-binding domain (RBD) and Subunit 2 (S2) that plays a role in the fusion process [3,4] (Figure 1). The SARS-CoV-2 spike protein is the major target for the development of COVID-19 vaccines.
While ACE2 is now well known as a ‘receptor’ to which the SARS-CoV-2 spike protein binds on human host cells in order to facilitate the membrane fusion and gain viral entry, the usual physiological function of ACE2 is not to serve as a membrane receptor to transduce intracellular signals. ACE2 is a type I integral membrane protein that functions as a carboxypeptidase, cleaving angiotensin II to angiotensin (1–7) and regulating blood pressure [24,25] (Figure 2).
However, ten years ago, Chen et al. [26] reported the intriguing findings showing that ACE2 acts as a membrane receptor for cell signal transduction in response to the spike protein of SARS-CoV (now also known as SARS-CoV-1, the virus that caused the SARS outbreak in 2002–2004) in the human lung alveolar epithelial cell line, A549. The spike protein of SARS-CoV-1 is 76–78% identical to that of SARS-CoV-2 [27]. In their study, it was shown that the binding of the full-length spike protein to ACE2 triggered the casein kinase II-dependent activation of activator protein-1 (AP-1) transcription factor and subsequent gene transcriptional events [26].
Their finding on SARS-CoV-1 [26] and ours on SARS-CoV-2 [21] indicate that the spike protein remarkably functionally converts ACE2 (that is normally a peptidase enzyme) into a membrane receptor for cell signaling that uses the spike protein as a ligand for its activation
Kuba et al. [28] showed that the injection of mice with recombinant SARS-CoV-1 spike protein reduced the ACE2 expression and worsened the acid-induced lung injury. In mice with an acid-induced lung injury, the recombinant SARS-CoV-1 spike protein dramatically increased angiotensin II, and the angiotensin receptor inhibitor losartan attenuated the spike protein-induced enhancement of lung injury [28].
Thus, these in vivo studies demonstrated that the spike protein of SARS-CoV-1 (without the rest of the virus) reduces the ACE2 expression, increases the level of angiotensin II, and exacerbates the lung injury.
The SARS-CoV-2 spike protein without the rest of the viral components has also been shown to activate cell signaling by Patra et al. [29]. The authors reported that the full-length SARS-CoV-2 spike protein expressed by the means of transient transfection, either in the human lung alveolar epithelial cell line A549 or in the human liver epithelial cell line Huh7.5, activated NF-κB and AP-1 transcription factors as well as p38 and ERK mitogen-activated protein kinases, releasing interleukin-6. This cell signaling cascade was found to be triggered by the SARS-CoV-2 spike protein downregulating the ACE2 protein expression, subsequently activating the angiotensin II type 1 receptor [29]. These experiments using transient transfection may reflect the intracellular effects of the spike protein that could be triggered by the RNA- and viral vector-based vaccines.
These results collectively reinforce the idea that human cells are sensitively affected by the extracellular and/or intracellular spike proteins though the activation of cell signal transduction.
...activated NF-κB and AP-1 transcription factors as well as p38 and ERK mitogen-activated protein kinases,...
Well, The NF-κB transcription factor was discovered 30 years ago and has since emerged as the master regulator of inflammation and immune homeostasis. It achieves this status by means of the large number of important pro- and antiinflammatory factors under its transcriptional control. source
AP-1 Transcription Factors Activator protein 1 (AP-1) is another family of bZIP transcription factors that play a central role in the regulation of neural gene expression by extracellular signals. The AP-1 family comprises multiple proteins that bind as heterodimers (and a few as homodimers) to the DNA sequence TGACTCA.Source
...but!
AP-1 (activating protein-1) is a collective term referring to dimeric transcription factors composed of Jun, Fos or ATF (activating transcription factor) subunits that bind to a common DNA site, the AP-1-binding site. As the complexity of our knowledge of AP-1 factors has increased, our understanding of their physiological function has decreased.Source
p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy.Source
Mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) is a key molecule in intracellular signal transducing pathways that transport extracellular stimuli from cell surface to nuclei.Source
Funny how the molecule chosen for the jab, which they're trying to shame/force on us, hits a cellular receptor which seems to light up the whole freaking immune system in fairly complex, systemic fashion, any time it hits an ACE2 receptor, for which it has affinity.
Next question is, what is the branching ratio for jabs of mRNA (running into a a helpful immune system cell to make antibodies vs. latching onto an ACE2-receptor and playing merry hell with the immune/cellular stress response)?
Are the effects of spike proteins interacting with ACE2 reversible, and is there a typical relaxation time for this to occur?
Is it mediated by the load ACE2 receptors either directly triggered, or cells responding to the proteins and cytokines released by the bound ACE2 receptors?
Anyone honest want to take a stab at this?