How Do Enveloped Viruses Exploit the Secretory Proprotein Convertases to Regulate Infectivity and Spread?

Abstract

Inhibition of the binding of enveloped viruses surface glycoproteins to host cell receptor(s) is a major target of vaccines and constitutes an efficient strategy to block viral entry and infection of various host cells and tissues. Cellular entry usually requires the fusion of the viral envelope with host plasma membranes. Such entry mechanism is often preceded by "priming" and/or "activation" steps requiring limited proteolysis of the viral surface glycoprotein to expose a fusogenic domain for efficient membrane juxtapositions. The 9-membered family of Proprotein Convertases related to Subtilisin/Kexin (PCSK) serine proteases (PC1, PC2, Furin, PC4, PC5, PACE4, PC7, SKI-1/S1P, and PCSK9) participate in post-translational cleavages and/or regulation of multiple secretory proteins. The type-I membrane-bound Furin and SKI-1/S1P are the major convertases responsible for the processing of surface glycoproteins of enveloped viruses. Stefan Kunz has considerably contributed to define the role of SKI-1/S1P in the activation of arenaviruses causing hemorrhagic fever. Furin was recently implicated in the activation of the spike S-protein of SARS-CoV-2 and Furin-inhibitors are being tested as antivirals in COVID-19. Other members of the PCSK-family are also implicated in some viral infections, such as PCSK9 in Dengue. Herein, we summarize the various functions of the PCSKs and present arguments whereby their inhibition could represent a powerful arsenal to limit viral infections causing the present and future pandemics.

Keywords: COVID-19; Furin; PCSK9; SARS-CoV-2; SKI-1/S1P; enveloped virus; pandemic; proprotein convertases.

Figure 1

Role of protease processing in SARS-CoV-2 entry. SARS-CoV-2 can enter through fusion at the plasma membrane or by endocytosis. The processing of the spike-protein at the plasma membrane by Furin at the S1/S2 site is favored while Furin & TMPRSS2 are involved in the processing at S2′, thereby inducing fusion. Furin cleavage at S1/S2 is not required to promote entry through endocytosis and Cathepsin L may cleave at S1/S2 and S2′ in endosomes.

Figure 2

Schematic representation of the cellular compartments and where Proprotein Convertases are active against viral substrates. Furin processes the coronavirus SARS-CoV-2 spike S in the TGN; SKI-1/S1P matures the arenavirus LASV and LCMV GP-Cs in the ER and late Golgi, respectively. The cleaved viral glycoproteins reach the cell surface. Arenaviruses do incorporate only cleaved GP-C into viral budding particles since treatment with the SKI-1/S1P inhibitor PF-429242 blocks GP-C processing and its incorporation into budding particles; SARS-CoV-2 can include both cleaved and uncleaved envelope glycoprotein spike S.