Fig. 5

Through a mechanism that requires only the prodomain/catalytic subunit of mature PCSK9 to bind ACE2, extracellular PCSK9 promotes the degradation of ACE2. This mechanism likely reduces ACE2 levels on the cell surface, inhibits cell-to-cell fusion, and potentially mitigates SARS-CoV-2 infection. This figure illustrates how extracellular PCSK9, and its gain-of-function variant D374Y in particular, substantially enhanced the degradation of ACE2. Necessary for the transportation of the PCSK9-LDLR complex to endosomes/lysosomes for degradation is the CHRD domain of PCSK9, particularly its M2 module. Surprisingly, the catalytic and/or prodomain of PCSK9 appear to be the critical domains for PCSK9 activity on ACE2, not the CHRD; this distinguishes ACE2 as a unique and novel PCSK9 target, quite distinct from the LDLR and MHC-I, which may partially explain this observation [52]