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.

Expression, Purification, and Characterization of Bovine Leukemia Virus-Like Particles Produced in Drosophila S2 Cells

“…On the other hand, we cannot exclude the possibility that a proportion of the EnvFm protein is cleaved by other intracellular proteases. In fact, cellular proteases play crucial roles by regulating the conformation of major viral proteins (67,68). The existence of undescribed hydrolysis sites for other cellular proteases cannot be ruled out (69).…”

The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer

“…This unexpected twist of events led us to study in detail the processing of the precursor of brain-derived neurotrophic factor (pro-brain-derived neurotrophic factor). Although it was already known that bioactive brain-derived neurotrophic factor (amino acids 129–247) production required cleavage at the R V RR 128 ↓HS site, we unexpectedly noticed that another earlier processing event occurred at R G L T 57 ↓SL, exhibiting a critical Arg and Leu at the P4 and P2 positions, respectively ( 35 ), a general motif later shown to be R -X- aliphatic -Z↓, where X and Z are variable amino acids ( 25 , 36 ). This observation led us to identify and clone the complementary DNA (cDNA) of the cognate type-I membrane-bound subtilase homologous to the bacterial pyrolysin, the eighth member of the PC family ( Fig.…”

“…Independently, a third PC, furin (gene FURIN ; PCSK3 ), was identified in 1989–1990 ( 21 , 22 ). This ubiquitously expressed type-I membrane-bound subtilase was found to cycle between the trans-Golgi network, cell surface, and endosomes ( 5 ) and is the major convertase of the constitutive secretory pathway implicated in the activation of a large variety of soluble and membrane-bound proteins, including growth factors, enzymes, receptors, toxins ( 5 , 23 , 24 ), and surface glycoproteins of infectious enveloped viruses, such as HIV-gp160 and the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 ( 25 , 26 ).…”

“…Independently, the same protease was found to process membrane-bound transcription factors, such as SREBPs 1 and 2, and was called “site 1 protease” (S1P) ( 37 ) and its gene “membrane-bound transcription factor protease site-1.” Thus, SKI-1/S1P regulates important physiological functions such as cholesterol and fatty acid metabolism ( 37 ), ER stress ( 38 ), bone metabolism ( 39 ), as well as the phosphorylation of mannose residues of proteins destined for lysosomal sorting ( 40 ). It was also realized that certain infectious hemorrhagic fever viruses exploit this mechanism to activate their surface glycoprotein and enhance their cellular infection and entry into various tissues ( 25 ).…”

“…The PCs, especially furin and SKI-1/S1P, play major roles in the activation of a number of enveloped viruses ( 25 ), including dengue virus (DENV). The latter is a single positive-stranded RNA virus of the family Flaviviridae , transmitted to human by the urban-adapted Aedes mosquitoes, which yearly infects >400 million individuals worldwide, resulting in ∼25,000 death/year mostly in children from southeast Asia ( 123 ).…”