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similar to a motif found in the catalytic site of enzymes involved in thiol
isomerization, like PDI or thioredoxin (Pinter
., 1997; Sanders, 2000). This
motif in the SU has been shown to be part of an autocatalytic isomerization
function of SU to destroy the initial bond between SU and TM generated during
Env synthesis and create an intra-SU bond inside the CXXC motif (Li
et al
et al
.,
2008; Wallin
et al
., 2004). This disulfide bond isomerization is crucial for the
fusogenicity of
-retrovirus (MLV) (Fenouillet
et al
., 2007).
3. Fusion activation by proteases
Some viruses use the protease activity of particular cellular enzymes localized in
the endosomes or at the cellular surface for activating their EnvGP. The Ebola
filovirus (for which the GP1-GP2 envelope glycoprotein is cleaved by the furine
in the producer cells) (Chandran
et al
., 2005; Schornberg
et al
., 2006), the HeV
(Pager and Dutch, 2005), NiV (Diederich
., 2009), or the SARS-CoV and
MHV-2 coronaviruses (for which the S spikes is not cleaved in the producer
cells) (Huang
et al
., 2005) require the
cysteins lysosomal proteases, the L or B cathepsine (CatL or CatB) for their entry
process. After virus uptake following angiotensin-converting enzyme 2 receptor
binding, cathepsin L-mediated proteolysis induces conformational changes in
the SARS-CoV S glycoprotein to trigger the endosomal membrane fusion
process (Simmons
et al
., 2006; Qiu
et al
., 2006; Simmons
et al
., 2005). Likewise, cleavage of the Ebola glycoprotein by
CatL cleavage removes a glycosylated glycan cap and mucin-like domain (MUC
domain) and exposes the conserved core residues implicated in receptor binding
(Chandran
et al
.,
2006). Entry of this virus is pH-dependent and associated with the cleavage of
GP by proteases, including CatL and/or CatB, in the endosome or cell mem-
brane, which is required for entry into the host cell. However, the precise role of
the cleavage of Ebola envelope glycoprotein, which is already cleaved intracel-
lularly during its exit, is uncertain. The cleavage of the GP to a stable form of
18 kDa of GP1 may increase binding, suggesting that the cleavage facilitates the
interaction with a cellular receptor (Dube
et al
., 2005; Hood
et al
., 2010; Lee
et al
., 2008; Schornberg
et al
., 2007).
Another possibility is that the CatB cleavage is required to facilitate the trigger-
ing of viral membrane fusion by destabilizing the prefusion conformation of
Ebola envelope glycoprotein (Wong
et al
., 2009; Kaletsky
et al
., 2010).
The cathepsins comprise a family of lysosomal protease enzymes whose
primary function (i.e., protein degradation) plays a critical role in normal cellular
homeostasis. Cathepsin L is one of the 11 members of human lysosomal cysteine
proteases (i.e., B, C, F, H, K, L, O, S, V, W, and X) that fall in the C1 family
(papain family) of the CA clan (Rossi
et al
., 2004). These enzymes were tradi-
tionally linked to nonspecific proteolytic activity within lysosomes. More
et al
