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. 2021 May 17;10:Chem Inf Sci-127. Originally published 2021 Feb 18. [Version 3] doi: 10.12688/f1000research.50850.3

Figure 9. Hypothesized mechanism of action of downregulated ERBB4 in SARS-CoV-2 infected cells.

Figure 9.

There are three possible mechanisms (1) SARS-CoV-2 an enveloped single-strand RNA virus, virions are internalized probably by receptor tyrosine kinase (EGFR) family receptor ERBB4 dependent macropinocytosis like SARS-CoV-1 (the process of macropinocytosis indicated in magenta circle). The cellular entry of SARS-CoV-2 involves binding to ERBB4 expressing AEC2 in the plasma membrane, macropinocytosis, and cathepsin based cleavage of the spike glycoproteins. The host transmembrane serine protease 2 (TMPRSS2) for spike priming and cathepsin cleaves spike glycoprotein S1 domain, permits fusion with endosomal membranes and release virions genome into the host cytoplasm; (2) Single-strand RNA translated polypeptides cleaved by the 3cLpro of SARS-CoV-2 possibly attached with mitochondrial ERBB4 and involve viral replication through MAPK signaling pathway. Then, the cell to cell spread action, the replicated SARS-CoV-2 attached to the uninfected AEC2 receptor and then restart macropinocytosis; (3) The part of S2 domain presents peptides into antigen-presenting cells (APC) to modulate host immune system through NFkB- signaling.