1.G.20 The Hantavirus Gc Envelope Fusion Glycoprotein (Gc-EFG) Family 

Hantaviruses cause hantavirus pulmonary syndrome or hemorrhagic fever with renal syndrome in humans. To enter cells, hantaviruses fuse their envelope membrane with host cell membranes. The Gc envelope glycoprotein is the viral fusion protein sharing characteristics with class II fusion proteins (Barriga et al. 2016). The ectodomain of class II fusion proteins is composed of three domains connected by a stem region to a transmembrane anchor in the viral envelope. These fusion proteins can be inhibited through exogenous fusion protein fragments spanning domain III (DIII) and the stem region. Such fragments are thought to interact with the core of the fusion protein trimer during the transition from its pre-fusion to its post-fusion conformation. Barriga et al. 2016 predicted and generated recombinant DIII and stem peptides to test whether these fragments inhibit hantavirus membrane fusion and cell entry. Recombinant ANDV DIII was soluble, presented disulfide bridges and beta-sheet secondary structure, supporting the in silico model. Using DIII and the C-terminal part of the stem region, the infection of cells by ANDV was blocked up to 60% when fusion of ANDV occurred within the endosomal route, and up to 95% when fusion occurred with the plasma membrane. Furthermore, the fragments impaired ANDV glycoprotein-mediated cell-cell fusion, and cross-inhibited the fusion mediated by the glycoproteins from Puumala virus (PUUV). The Gc fragments interfered in ANDV cell entry by preventing membrane hemifusion and pore formation, retaining Gc in a non-resistant homotrimer stage, as described for DIII and stem peptide inhibitors of class II fusion proteins.


 

References:

Barriga, G.P., F. Villalón-Letelier, C.L. Márquez, E.A. Bignon, R. Acuña, B.H. Ross, O. Monasterio, G.A. Mardones, S.E. Vidal, and N.D. Tischler. (2016). Inhibition of the Hantavirus Fusion Process by Predicted Domain III and Stem Peptides from Glycoprotein Gc. PLoS Negl Trop Dis 10: e0004799.

Hulswit, R.J.G., G.C. Paesen, T.A. Bowden, and X. Shi. (2021). Recent Advances in Bunyavirus Glycoprotein Research: Precursor Processing, Receptor Binding and Structure. Viruses 13:.

Jin, M., J. Park, S. Lee, B. Park, J. Shin, K.J. Song, T.I. Ahn, S.Y. Hwang, B.Y. Ahn, and K. Ahn. (2002). Hantaan virus enters cells by clathrin-dependent receptor-mediated endocytosis. Virology 294: 60-69.

Pekosz, A., C. Griot, N. Nathanson, and F. Gonzalez-Scarano. (1995). Tropism of bunyaviruses: evidence for a G1 glycoprotein-mediated entry pathway common to the California serogroup. Virology 214: 339-348.

Plassmeyer, M.L., S.S. Soldan, K.M. Stachelek, J. Martín-García, and F. González-Scarano. (2005). California serogroup Gc (G1) glycoprotein is the principal determinant of pH-dependent cell fusion and entry. Virology 338: 121-132.

Shtanko, O., R.A. Nikitina, C.Z. Altuntas, A.A. Chepurnov, and R.A. Davey. (2014). Crimean-Congo hemorrhagic fever virus entry into host cells occurs through the multivesicular body and requires ESCRT regulators. PLoS Pathog 10: e1004390.

Suda, Y., S. Fukushi, H. Tani, S. Murakami, M. Saijo, T. Horimoto, and M. Shimojima. (2016). Analysis of the entry mechanism of Crimean-Congo hemorrhagic fever virus, using a vesicular stomatitis virus pseudotyping system. Arch Virol 161: 1447-1454.

Xiao, X., Y. Feng, Z. Zhu, and D.S. Dimitrov. (2011). Identification of a putative Crimean-Congo hemorrhagic fever virus entry factor. Biochem. Biophys. Res. Commun. 411: 253-258.

Examples:

TC#NameOrganismal TypeExample
1.G.20.1.1

Envelope poly-glycoprotein of 1135 aas and 3 - 5 TMSs, Gc-GP.  Glycoprotein N (Hanta G!; N-terminal domain) and Glycoprotein C (Hanta G2; C-terminal domain) interact with each other after cleavage of the full length protein, present on the surface of the virion. They attach the virion to host cell receptors to induce virion internalization predominantly through clathrin-dependent endocytosis. Gc-GP also promotes fusion of the viral membrane with the host endosomal membrane after endocytosis of the virion (Jin et al. 2002).

Gc-GP of Hantaan virus (Korean hemorrhagic fever virus)

 
1.G.20.1.2

Polyprotein of 1432 aas and 5 - 7 TMSs.

Polyprotein of I612045 virus

 
1.G.20.1.3

M polyprotein, Gn-Gc-NSm, of 1403 aas and 5 - 7 TMSs.

Gn-Gc-NSm of Shamonda virus

 
1.G.20.1.4

The envelopment polyprotein, GP, of 1441 aas and 8 TMSs in a 1 (N-terminal) + 2 +4 + 1 (C-terminal) TMS arrangement. The precursor protein is processed to the glycoprotein (C-terminal) and glycoprotein (N-terminal) which interact with each other and are present at the surface of the virion. They are able to attach the virion to a cell receptor and to promote fusion of membranes after endocytosis of the virion (Plassmeyer et al. 2005; Pekosz et al. 1995; Hulswit et al. 2021).

GP of Bunyavirus La Crosse

 
Examples:

TC#NameOrganismal TypeExample
1.G.20.2.1

Envelope glycoprotein of 1684 aas and 5 - 8 TMSs, Env-GP, including Gn and Gc (Xiao et al. 2011).  Blocking transport out of multivesicular bodies still allowed virus entry while preventing vesicular acidification, required for membrane fusion, trapping virions in the MVBs (Shtanko et al. 2014).  Entry is dependent on the CCHFV envelope GP (Suda et al. 2016).

Env-GP of Crimean-Congo hemorrhagic fever virus (CCHFV)

 
1.G.20.2.2

GPC glycoprotein of 1296 aas and 3 - 4 TMSs.  May function in evasion or tolerance by the virus to the host immune response. 

GPC of the Erve virus

 
1.G.20.2.3

M-protein, Gn-Gc-NSm, of 1549 aas and 5 - 7 TMSs.

Gn-Gc-NSm of Simbu virus