Fig. 5

SARS-CoV-2 spike protein binding with ACE2 initiates transcriptional events which modify chondroitin sulfation through activation of phospho-p38 MAPK. This schematic presents the signaling mechanism by which the SARS-CoV-2 spike protein receptor-binding domain (SPRBD) interacts and initiates the transcriptional events which lead to increased chondroitin sulfate in airway epithelial cells and in Covid-19 infected lung.¹ The activation of phospho-p38 MAPK and phospho-SMAD3 lead to increased expression of CHST15 and CHST11. Phospho-p38 MAPK leads to N-terminal phosphorylation of Rb and enhanced Rb binding with E2F1, which reduces ARSB promoter binding with E2F1 and reduces ARSB expression. Additional effects may arise from ACE2-SPRBD binding, due to reduced availability of ACE2 for other biochemical reactions, including the conversion of AngII to Ang1-7. AngII interaction with the angiotensin II receptor type 1 (AT1R) increases phospho-p38 MAPK, and increased availability of AngII may contribute to the observed downstream effects of p38 MAPK on transcription. The altered balance between AngII-induced vasoconstriction and Ang1-7 vasodilatation, following interaction with the G-protein coupled Mas receptor, may have additional pathophysiological consequences. ACE2 angiotensin-converting enzyme 2, AngII angiotensin II, ARSB arylsulfatase B, AT1R angiotensin II receptor type 1, AT2R angiotensin II receptor type 2, CHST carbohydrate sulfotransferase, Mas Ang1-7 receptor, pRb retinoblastoma protein, SMAD Suppressor of Mothers against Decapentaplegic, SPRBD SARS-CoV-2 spike protein receptor binding domain