Inhibition of endocytic recycling of ACE2 by SARS-CoV-2 S protein partially explains multiple COVID-19 related diseases caused by ACE2 reduction

SNX27-mediated endocytic recycling of GLUT1 is suppressed by SARS-CoV-2 spike, possibly explaining neuromuscular disorders in patients with COVID-19

“…Previously in this Journal, we described that inhibition of sorting nexin 27 (SNX27)- mediated endocytic recycling of angiotensin-converting Enzyme 2 (ACE2) by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) partially explains multiple Coronavirus Disease 19 (COVID-19) related diseases caused by ACE2 reduction ( 1 ). Together with retromer, SNX27 mediates endocytic recycling of multiple membrane proteins including glucose transporter type 1 (GLUT1) from endosomes to the plasma membrane ( 2 , 3 ).…”

“…1 A, bacterial expressed GST-tagged SNX27 (GST-SNX27) but not GST could pull down GFP-tagged GLUT1 (GLUT1-GFP). Our previous study found that SARS-CoV-2 S interacted with PSD95/Dlg1/ZO-1 (PDZ) domain of SNX27 ( 1 ). Since both S and GLUT1 interacted with PDZ domain of SNX27 ( 1 , 3 ), we hypothesized that SARS-CoV-2 S might compete with GLUT1 for associating with SNX27.…”

“…Our previous study found that SARS-CoV-2 S interacted with PSD95/Dlg1/ZO-1 (PDZ) domain of SNX27 ( 1 ). Since both S and GLUT1 interacted with PDZ domain of SNX27 ( 1 , 3 ), we hypothesized that SARS-CoV-2 S might compete with GLUT1 for associating with SNX27. To test this hypothesis, we performed GST pulldown experiments and found that overexpression of GFP-tagged S (GFP-S) but not GFP reduced the binding ability of GLUT1-GFP to GST-SNX27 ( Fig.…”

“…To fulfill the endocytic recycling, PDZ domain of SNX27 associates with Vps26 (Vps26A or Vps26B), a key component of retromer ( 2 ). Because both SARS-CoV-2 S and Vps26 associated with PDZ domain of SNX27 ( 1 , 2 ), we wonder whether SARS-CoV-2 S abrogates the protein-protein interaction between Vps26A and SNX27 by competing with Vps26 for associating with SNX27. To test this hypothesis, we performed GST pulldown experiments and found that overexpression of GFP-S but not GFP reduced the binding ability of GFP-tagged Vps26A (Vps26A-GFP) to PDZ domain or full length of SNX27 ( Fig.…”

“…Spike-based SARS-CoV-2 vaccines including BNT162b2 from BioNTech and mRNA-1273 from Moderna have been administrated globally. Previously, we discussed that side effects of S-based SARS-CoV-2 vaccine, such as myocarditis and pericarditis, may due to the reduction of ACE2 recycling by S ( 1 ). Cervical dystonia and ataxia were occasionally reported after spike-based SARS-CoV-2 mRNA vaccination ( 8 , 9 , 10 ).…”