Host cell proteases: critical determinants of coronavirus tropism and pathogenesis

By J. Millet, Gary R. Whittaker. Virus Research, 2014

857 citations recorded by the source corpus.

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.

Subfields: Animal Science and Zoology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/2f03862fdf55d43d4a2c868bcf9ac34b6519d2a0

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Citations in the corpus

Cell entry mechanisms of SARS-CoV-2 (2020, background): “Last, the cell entry process of SARS-CoV-2 can be blocked using inhibitors that target the protease activators (47).”
Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak (2020, neutral): “Interestingly, aside from MERS-CoV, similar sequence patterns to the SARS-CoV-2 were also presented in somemembers of Alphacoronavirus, Betacoronavirus, and Gammcoronavirus [19], raising an interesting question regarding whether this furin sequence motif in SARSCoV-2 might be derived from those exis”
The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status (2020, background): “For SARS-CoV, the cleavage of trimer S protein is triggered by the cell surface-associated transmembrane protease serine 2 (TMPRSS2) [39] and cathepsin [40], while the possible molecules facilitated membrane invagination for SARS-CoV-2 endocytosis are still unclear.”
Prefusion structure of a human coronavirus spike protein (2016, background): “Coronavirus S proteins also have a secondary cleavage site, termed S2′ (Arg900) 5 , adjacent to the viral fusion peptide (amino acids 901-918) 17 (Fig.”
COVID-19: Epidemiology, Evolution, and Cross-Disciplinary Perspectives (2020, neutral): “Cathepsins, ubiquitous lysosomal enzymes with a rather broad substrate specificity, cleave S during virus entry [66].”
Structure, Function, and Evolution of Coronavirus Spike Proteins (2016, background): “, cathepsin L and cathepsin B) after virus endocytosis in virus-targeting cells (120) (Figure 7).”
Glycan shield and epitope masking of a coronavirus spike protein observed by cryo-electron microscopy (2016, background): “After virion uptake by target host cells, cleavage at the S 2 ′ site (next to the putative fusion peptide) is required for fusion activation of all coronavirus S proteins, so that they can subsequently transition to the postfusion conformation [15] [16] [17] .”
Glycan Shield and Fusion Activation of a Deltacoronavirus Spike Glycoprotein Fine-Tuned for Enteric Infections (2017, background): “endo-lysosomes, and explain the fact that trypsin-like TMPRSS proteases can also 337 trigger both proteins(10, 15).”
Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein (2020, background): “For all CoVs, S is further cleaved by host proteases at the so-called S2 0 site located immediately upstream of the fusion peptide (Madu et al., 2009; Millet and Whittaker, 2015).”
Further Evidence for Bats as the Evolutionary Source of Middle East Respiratory Syndrome Coronavirus (2017, background): “Other processes are also important, such as the activation of the spike protein by host proteases (18), but the ability of S1 to bind with a host receptor is a critical step in the emergence pathway—and it can be quickly altered by a single recombination event.”
TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells (2020, background): “Cleavage at the S1/S2 site may be crucial for conformational changes required for receptor binding and/or subsequent exposure of the S2 9 site to host proteases at the stage of virus entry (reviewed in references 6, 7, and 8).”
The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade (2020, background): “In this case, it was reported that following receptor binding the Sprotein is cleaved at a conserved sequence AYT↓M (located 10 aa downstream of SLLR-ST) by target cells’ proteases such as elastase, cathepsin L or TMPRSS2 (Bosch et al., 2008; Matsuyama et al., 2010, 2005; Millet and Whittaker, 2015)”
Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology (2020, positive): “…S harbors a polybasic furin cleavage site at the S 1 /S 2 boundary between the two S functional sub-units, which is unique within the sarbecovirus subgenus and key for infectivity and virulence (Hoffmann et al., 2020a; 2020b; Lau et al., 2020; Millet and Whittaker, 2015; Walls et al., 2020).”