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Review
. 2013 Dec;100(3):605-14.
doi: 10.1016/j.antiviral.2013.09.028. Epub 2013 Oct 8.

Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research

Graham Simmons  1 , Pawel Zmora, Stefanie Gierer, Adeline Heurich, Stefan Pöhlmann
Affiliations
Review

Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research

Graham Simmons et al. Antiviral Res. 2013 Dec.

Abstract

The severe acute respiratory syndrome (SARS) pandemic revealed that zoonotic transmission of animal coronaviruses (CoV) to humans poses a significant threat to public health and warrants surveillance and the development of countermeasures. The activity of host cell proteases, which cleave and activate the SARS-CoV spike (S) protein, is essential for viral infectivity and constitutes a target for intervention. However, the identities of the proteases involved have been unclear. Pioneer studies identified cathepsins and type II transmembrane serine proteases as cellular activators of SARS-CoV and demonstrated that several emerging viruses might exploit these enzymes to promote their spread. Here, we will review the proteolytic systems hijacked by SARS-CoV for S protein activation, we will discuss their contribution to viral spread in the host and we will outline antiviral strategies targeting these enzymes. This paper forms part of a series of invited articles in Antiviral Research on "From SARS to MERS: 10years of research on highly pathogenic human coronaviruses.''

Keywords: Cathepsin L; MERS; Protease; SARS; Spike protein; TMPRSS2.

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Figures

Fig. 1
Fig. 1
Domain organization of the SARS-coronavirus spike protein. The surface unit, S1, contains an N-terminal signal peptide, which targets the protein for import into the constitutive secretory pathway, and a receptor binding domain (RBD), which mediates binding to ACE2. The transmembrane unit, S2, harbors the functional elements required for membrane fusion, a fusion peptide and two heptad repeats. It also contains a transmembrane domain, which anchors the protein within cellular membranes, and a cytoplasmic tail, which is required for appropriate intracellular trafficking of the spike protein. Arrows indicate amino acid positions cleaved by cellular proteases.
Fig. 2
Fig. 2
Routes employed by the SARS-coronavirus for entry into target cells. The SARS-coronavirus can employ two routes for host cell entry, which are determined by the localization of the proteases required for activation of the SARS-coronavirus spike protein. Binding of SARS-coronavirus to the cellular receptor, ACE2, can result in uptake of virions into endosomes, where the spike protein is activated by the pH dependent cysteine protease cathepsin L. Activation of the spike protein by cathepsin L can be blocked by lysosomotropic agents, like bafilomycin A1 and ammonium chloride, which indirectly inhibit cathepins L activity by interfering with endosomal acidification, or by compounds which directly block the proteolytic activity of cathepsin L, like MDL28170. Alternatively, the spike protein can be activated by TMPRSS2 at (or close to) the cell surface, resulting in fusion of the viral membrane with the plasma membrane.
Fig. 3
Fig. 3
Domain organization of TMPRSS2 and HAT. TMPRSS2 and HAT, both members of the type II transmembrane serine protease family, contain an N-terminal cytoplasmic domain, a transmembrane domain, a stem region and a catalytic domain. The stem region of TMPRSS2 harbors a LDL-receptor class A domain and a scavenger receptor cysteine-rich domain (SRCR), while sperm protein, enterokinase and agrin (SEA) domain is present in the stem region of HAT. The catalytic domains of both proteases contain a catalytic triad, consisting of a serine (S), histidine (H) and aspartate (D) residue, which is essential for enzymatic activity. Both enzymes are synthesized as inactive precursors, zymogens, and transit into their active form upon cleavage between the pro- and catalytic domain (indicated by an arrow). In the mature enzyme, the catalytic domain and the remainder of the protein covalently associated via a disulfide bond.
Fig. 4
Fig. 4
Role of proteases in SARS-coronavirus entry and lung pathogenesis. The dipeptidyl peptidase ACE converts angiotensin 1 (ANG1) into ANG2, which promotes severe lung injury (and thus development of SARS) via the AT1R receptor. Binding of ANG2 to AT2R and conversion of ANG2 into ANG-1(1–7) by ACE2 protect from lung injury. The binding of the SARS-coronavirus spike protein to ACE2 induces ACE2 shedding by ADAM17 and is associated with increased cellular uptake of SARS-coronavirus particles. ADAM17 activity is known to be regulated by AT1R via intracellular calcium levels and by phorbol esters like PMA, which induce phosphorylation of the ADAM17 cytoplasmic tail via PKC activity. In addition, calmodulin is known to associate with the ACE2 cytoplasmic tail and may regulate ACE2 shedding via PKC-dependent activation of ADAM17. TMPRSS2 also cleaves ACE2 and it was proposed that cleavage increases SARS-coronavirus entry. Whether ACE2 cleavage by TMPRSS2 results in ACE2 shedding remains to be investigated. The figure was partially adapted from Imai et al., Cell. Mol. Life Sci., 2007.
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