SARS-CoV-2 Spike Protein Downregulates Cell Surface α7nAChR through a Helical Motif in the Spike Neck, 2023, Tillman et al.

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SARS-CoV-2 Spike Protein Downregulates Cell Surface α7nAChR through a Helical Motif in the Spike Neck
Tommy S. Tillman; Qiang Chen; Vasyl Bondarenko; Jonathan A. Coleman; Yan Xu; Pei Tang

A deficiency of the functional α7 nicotinic acetylcholine receptor (α7nAChR) impairs neuronal and immune systems. The SARS-CoV-2 spike protein (S12) facilitates virus cell entry during COVID-19 infection and can also independently disrupt cellular functions.

Here, we found that S12 expression significantly downregulated surface expression of α7nAChR in mammalian cells. A helical segment of S12 (L1145-L1152) in the spike neck was identified to be responsible for the downregulation of α7nAChR, as the mutant S12AAA (L1145A-F1148A-L1152A) had minimal effects on surface α7nAChR expression. This S12 segment is homologous to the α7nAChR intracellular helical motif known for binding chaperone proteins RIC3 and Bcl-2 to promote α7nAChR surface expression. Competition from S12 for binding these proteins likely underlies suppression of surface α7nAChR.

Considering the critical roles of α7nAChR in cellular functions, these findings provide a new perspective for improving mRNA vaccines and developing treatment options for certain symptoms related to long COVID.

Link | PDF (ACS Chemical Neuroscience)

 

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This is from a year ago, but I thought it was interesting. Doesn't seem to have found much interest or been replicated though.

 

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Introduction quotes —

α7nAChR is widely expressed across the human body in both neuronal and non-neuronal cells. In the brain, it is expressed on both pre- and postsynaptic membranes and particularly in regions implicated in cognitive function, such as the hippocampus and cortex. α7nAChR is also expressed in immune cells, such as macrophages, that form the basis for some of the known α7nAChR-mediated anti-inflammatory effects. A deficiency of functional α7nAChR is implicated in neuropsychic diseases and disrupts the cholinergic antiinflammatory pathway.

In this study, we discovered that the SARS CoV-2 spike protein ectodomain (S12) can significantly suppress expression of α7nAChR in mammalian cells. The suppression has a much more profound impact on surface α7nAChR than that in the intracellular stores, implying that S12 mainly affects receptor trafficking. The suppression effect results from S12 coexpression with α7nAChR instead of the S12 presence in extracellular milieu.

Additionally, we have identified a segment in S2 that is homologous to the hydrophobic helical motif in the α7nAChR intracellular domain, which is responsible for binding the receptor chaperone proteins, such as resistance to inhibitor of cholinesterase-3 (RIC3) and antiapoptotic Bcl-2 family proteins.

 

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Discussion quotes —

A major discovery from the current study is the downregulation of surface α7nAChR by the spike protein ectodomain S12. The extent of the downregulation is profound, with more than one-third of surface α7nAChR and more than half of the functional α7nAChR.

Deficiency of functional α7nAChR in the hippocampus and other brain regions is associated with neuropsychiatric disorders with numerous deleterious symptoms, including cognitive impairments and sensory processing deficits.

a significant reduction of α7nAChR can potentially impair not only cognitive performance and sensory processing but also normal immune response to inflammation.

Another major discovery from the current study is the underlying mechanism of how S12 downregulates surface α7nAChR. It is intriguing to learn that a helical segment (L1145-L1152) in the spike neck is homologous with the α7nAChR helical segment (L411-V418) responsible for binding chaperones for receptor assembly and trafficking. Eliminating the possibility for S12 binding α7nAChR chaperones (RIC-3 and antiapoptotic Bcl-2 proteins) in S12 AAA restored surface α7nAChR close to normal. The result supports a competition mechanism for downregulating surface α7nAChR by S12.

It is worth mentioning that the L1145-L1152 segment is conserved in all variants of SARS-CoV-2. The predominant SARS-CoV-2 mRNA vaccines encode the full-length spike protein, including the L1145-L1152 segment. For new versions of SARS-CoV-2 mRNA-based vaccines, one should consider mutating the L1145-L1152 segment, as we did for S12AAA , to prevent potential adverse effects.