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SARS-CoV-2 刺突蛋白通过刺突颈部的螺旋基序下调细胞表面 α7nAChR。

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

机构信息

Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.

Department of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.

出版信息

ACS Chem Neurosci. 2023 Feb 15;14(4):689-698. doi: 10.1021/acschemneuro.2c00610. Epub 2023 Feb 6.

DOI:10.1021/acschemneuro.2c00610
PMID:36745901
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9923440/
Abstract

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 S12 (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.

摘要

功能性 α7 型烟碱型乙酰胆碱受体 (α7nAChR) 的缺乏会损害神经系统和免疫系统。SARS-CoV-2 刺突蛋白 (S12) 在 COVID-19 感染期间促进病毒进入细胞，也可以独立破坏细胞功能。在这里，我们发现 S12 表达显著下调了哺乳动物细胞表面 α7nAChR 的表达。刺突颈部的一个螺旋片段 (L1145-L1152) 被确定为负责下调 α7nAChR 的原因，因为突变的 S12 (L1145A-F1148A-L1152A) 对表面 α7nAChR 的表达几乎没有影响。该 S12 片段与 α7nAChR 细胞内螺旋基序同源，已知该基序与伴侣蛋白 RIC3 和 Bcl-2 结合，促进 α7nAChR 表面表达。S12 与这些蛋白结合的竞争可能是抑制表面 α7nAChR 的基础。考虑到 α7nAChR 在细胞功能中的关键作用，这些发现为改进 mRNA 疫苗和开发与长期 COVID 相关的某些症状的治疗方案提供了新的视角。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/84796cc0a90d/cn2c00610_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/efd7eb0e37ca/cn2c00610_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/dfe55a79e91e/cn2c00610_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/e062126cd112/cn2c00610_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/152e0b98583a/cn2c00610_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/100ae4c2cc28/cn2c00610_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/9f9a1371c82c/cn2c00610_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/84796cc0a90d/cn2c00610_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/efd7eb0e37ca/cn2c00610_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/dfe55a79e91e/cn2c00610_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/e062126cd112/cn2c00610_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/152e0b98583a/cn2c00610_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/100ae4c2cc28/cn2c00610_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/9f9a1371c82c/cn2c00610_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4467/9936551/84796cc0a90d/cn2c00610_0007.jpg

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