Figure 3:

Proposed roles for alternative receptors and mediators of viral entry into β cells based on studies in other cell types. (A) The mature virion binds to its host cell receptor, which may be CD147 (left), GRP78 (centre) or ACE2 (right). If the host cell receptor is ACE2, SARS-CoV-2-spike-ACE2 binding may be facilitated by GRP78 or HS/HSPG. ADAM17 may be involved in ACE2-mediated SARS-CoV-2 entry in several ways. On one hand, ADAM17 cleaves csACE2, releasing sACE2, which can impede SARS-CoV-2-receptor binding. On the other hand, ADAM17 can cleave and activate cytokines for release, which may upregulate viral entry mediators. On the whole, the net impact of ADAM17 on viral entry is unclear. (B) Before membrane fusion, the spike protein must be processed. After S1/S2 cleavage by furin (which can also occur during viral production), NRP1 can stabilise the SARS-Cov-2-S1-CendR motif to increase the rate of viral spike processing. S2’ cleavage may occur by another host protease in the absence of TMPRSS2. (C) Alternatively, rather than viral envelope-host cell membrane fusion, the SARS-CoV-2-receptor complex can be taken up via receptor-mediated endocytosis. CTSL in the endosome cleaves SARS-CoV-2-spike at a site distinct from the S1/S2 boundary and S2’ site. Viral entry is complete when the viral envelope fuses with the host cell surface membrane or endosomal membrane.