Figure 1.

Routes of coronavirus entry. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) contains a transmembrane spike (S) glycoprotein, which is important for (i) host cell receptor binding by the S1 subunit, and (ii) subsequent S2 subunit activation via S protein proteolytic cleavage to mediate virus-cell fusion and entry. There are two major routes of viral activation: Route A: When angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) are co-expressed on the host cell surface, SARS-CoV-2 will bind to ACE2 and become activated by TMPRSS2 via proteolytic cleavage to mediate viral-cell fusion. Route B: If there is no surface expression of a protease, SARS-CoV-2 can undergo endocytosis, endosomal maturation (mediated by two pore channel subtype 2 (TPC2) and phosphatidylinositol 3-phosphate 5-kinase (PIKfyve)), followed by cleavage with pH-dependent cysteine protease cathepsin L (CTSL). Figure created with BioRender.com.