Figure 4:

Hypothesized interaction of ACE2, ADAM17, CD147 and GRP78 under conditions of elevated pro-inflammatory cytokines and ER stress. In patients with COVID-19, pancreatic endocrine cells are bathed in cytokines derived from the circulation. This state (A) upregulates ACE2 gene expression and (B) ER stress, which causes (C) an increase in ADAM17 mRNA levels. (D) ER stress also increases GRP78 mRNA levels, mediated by CD147. The subsequent increase in GRP78 protein results in (E) missorting and translocation of GRP78 to the cell surface, where it may (F) act as an alternative receptor or ACE2 cofactor during SARS-CoV-2 entry. (G) GRP78 is also involved in ACE2 trafficking to the plasma membrane. Additionally, GRP78 (H) protects ADAM17 from inhibition, which allows ADAM17 to (I) cleave plasma membrane bound ACE2 at an increased rate, thereby elevating soluble ACE2 levels, which may (J) bind to the spike protein and inhibit SARS-CoV-2 entry. At the same time, (K) ER stress upregulates CD147. The consequent increase in CD147 at the cell surface can (L) increase CD147-mediated SARS-CoV-2 entry.