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. 2020 Nov 27:10.2217/pgs-2020-0092. doi: 10.2217/pgs-2020-0092

Figure 1. The ACE2-based-severe acute respiratory syndrome coronavirus-2 entry machinery and its regulation by genetic and epigenetic factors.

Figure 1.

(A) SARS-CoV-2 binds to membrane-bound ACE2 to enter the host cells. This interaction with ACE2 is mediated via the spike (S) glycoprotein on SARS-CoV-2 surface. During infection, the S protein is cleaved by furin into subunits, S1 and S2. S protein priming is essential for entry of SARS-CoV-2 and relies upon TMPRSS2. The ectodomain of ACE2 can be shed by ADAM-17 generating sACE2. CALM interacts with ACE2 and inhibits shedding of its ectodomain. AR upregulates TMPRSS2 expression, whereas ERs potentially downregulate ACE2 expression. (B) Genetic and epigenetic variations that affect the expression and activity of ACE2-based-SARS-CoV2 entry machinery and strengthen the interaction of SARS-CoV-2 with ACE2 conferring increased infectivity risk. These include: ACE2 variants that boost the interaction with S protein, decreased ACE2 methylation that increase ACE2 transcription and available membrane ACE2, TMPRSS2 increased expression variants that enhance S protein priming, FURIN increased expression variants that induce S1/S2 cleavage, ADAM-17 loss-of-function variants and ADAM-17 downregulation by miRNAs that reduce ADAM-17 mediated ACE2 ectodomain shedding and variations in AR gene that increase AR transcription and promote TMPRSS2 expression. (C) Genetic and epigenetic variations that affect the expression and activity of ACE2-based-SARS-CoV-2 entry machinery and inhibit the interaction of SARS-CoV-2 with ACE2 conferring reduced infectivity risk. These include ACE2 variants that inhibit the interaction with S protein, increased ACE2 methylation and ACE2 downregulation by miRNAs that reduce available membrane ACE2, TMPRSS2 variants within AR element, TMPRSS2 fusion with ERG and increased TMPRSS2 methylation that decrease S protein priming, ADAM-17 increased expression variants that enhance ADAM-17 mediated ACE2 ectodomain shedding and increase sACE2 that binds SARS-CoV-2 thus preventing its entry to host cell, variations in AR gene that reduce AR transcription and signaling for TMPRSS2 expression and variations in ESR genes that reduce ER transcription and signaling for ACE2 expression. Upregulation is represented by green. Downregulation is represented by red.

sACE2: Soluble ACE2; SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2.

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