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Review
. 2015 Apr 16:202:120-34.
doi: 10.1016/j.virusres.2014.11.021. Epub 2014 Nov 22.

Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis

Jean Kaoru Millet  1 , Gary R Whittaker  2
Affiliations
Review

Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis

Jean Kaoru Millet et al. Virus Res. .

Abstract

Coronaviruses are a large group of enveloped, single-stranded positive-sense RNA viruses that infect a wide range of avian and mammalian species, including humans. The emergence of deadly human coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) have bolstered research in these viral and often zoonotic pathogens. While coronavirus cell and tissue tropism, host range, and pathogenesis are initially controlled by interactions between the spike envelope glycoprotein and host cell receptor, it is becoming increasingly apparent that proteolytic activation of spike by host cell proteases also plays a critical role. Coronavirus spike proteins are the main determinant of entry as they possess both receptor binding and fusion functions. Whereas binding to the host cell receptor is an essential first step in establishing infection, the proteolytic activation step is often critical for the fusion function of spike, as it allows for controlled release of the fusion peptide into target cellular membranes. Coronaviruses have evolved multiple strategies for proteolytic activation of spike, and a large number of host proteases have been shown to proteolytically process the spike protein. These include, but are not limited to, endosomal cathepsins, cell surface transmembrane protease/serine (TMPRSS) proteases, furin, and trypsin. This review focuses on the diversity of strategies coronaviruses have evolved to proteolytically activate their fusion protein during spike protein biosynthesis and the critical entry step of their life cycle, and highlights important findings on how proteolytic activation of coronavirus spike influences tissue and cell tropism, host range and pathogenicity.

Keywords: Cleavage activation; Coronavirus; Pathogenesis; Protease; Spike protein; Tropism.

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Figures

Fig. 1
Fig. 1
Structural features of coronavirus spike (S) envelope glycoprotein. (A) Diagram of a coronavirus virion with the main structural proteins depicted. The S protein assembles in trimers and projects outward from the virion to form a crown-like structure. The hemagglutinin esterase protein (HE) is found only in lineage A betacoronaviruses. (B) Diagram of coronavirus S protein with the two well-defined cleavage sites, S1/S2 and S2′ (arrows). The S protein is composed of two subunits, the S1 receptor-binding subunit, and the S2 fusion subunit. NTD: N-terminal domain of S1, C-domain: C-terminal domain of S1, L: linker region between S1/S2 and S2′ sites, FP: putative fusion peptide, HR1: heptad repeat 1, HR2: heptad repeat 2, TM: transmembrane domain, E: endodomain. Not drawn to scale.
Fig. 2
Fig. 2
Host cell proteases involved in activating the coronavirus spike (S) protein. (A) Schematic of a protease cleavage site and substrate binding pocket. The sites within the protease that accommodate substrate residues are designated with the letter S. The residues of the substrate protein involved in recognition and proteolytic processing are denoted with the letter P. The scissile bond is cleaved by the protease and the residues involved in this bond are denoted P1–P1′. (B) Structures of three common host cell proteases known to activate coronavirus S: crystal structures of trypsin (PDB: 2PTN), furin (PDB: 1P8J), and the pro-form of cathepsin L (PDB: 1CJL). (C) Diagram of a coronavirus life cycle and the various host cell proteases known to cleave and activate some coronavirus S proteins. Note that for certain coronaviruses, fusion can occur directly at the plasma membrane.
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