SARS-CoV‑2 Spike Protein Downregulates Cell Surface α7nAChR through a Helical Motif in the Spike Neck

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.