Furin and Coronaviruses: lessons from invertebrate immunity?

I was motivated to pen some thoughts on Furins owing the ongoing Covid-19 pandemic. My research focuses on antimicrobial peptides (AMPs), which in Drosophila and other insects are commonly cleaved by Furin-like enzymes. Relatively little has been done to understand exactly how different Furins act, and what intracellular processes they can regulate; this is likely at least in part due to their potential to affect many cell processes simultaneously, making genetic approaches difficult and confusticating the interpretation of focused in vitro approaches.

What is Furin, and how does it relate to Sars-CoV-2?

The Sars-CoV-2 (Sars2) pandemic has resulted in a great deal of interest in the unique Furin cleavage site of the Sars2 spike protein [1-3]. Furins are subtilisin-like peptidases that cleave at a predictable multibasic cleavage site typically consisting of either an RXRR or RXKR motif. Humans encode many Furin-like enzymes including human Furin and numerous proprotein convertase subtilisin/kexin type (PCSK) enzymes [4].  It has been shown that even within the RXRR motif Furins, there is substrate specificity depending on what the X is, and also some variation in preference for whether the terminal residues are RR or KR (e.g. PCSK3) [4-5]. However there is also residual activity of human Furin on RXXR sites in general (NEB: Furin), suggesting these enzymes are not absolutely specific. These cleavages are thought to occur either at the cell membrane, at the golgi, or in vesicles during subcellular trafficking [6].

There is some evidence that Sars2 infectivity is affected by the presence of the Sars2 Furin site (RRAR). In an African green monkey kidney epithelium cell line (Vero E6), loss of the Furin cleavage site is associated with improved infectivity [3]. However the direction of change owing to the presence/absence of this cleavage site in human cells and in more relevant tissues (like lung epithelium) is not clear. What is known is that such Furin sites are not unique to Sars2, but also found in MERS-CoV (RXVR), HCOV-OC43 (RSRR), and HKU1-CoV (RKRR) [7]. So it seems like Furin sites are maintained in many CoVs, despite a reduced efficiency of Furin site-containing Sars2 in Vero cells.

Drosophila as a model for Furin evolution and specificity...

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