Recent Advances in Bunyavirus Glycoprotein Research: Precursor Processing, Receptor Binding and Structure

Abstract

The Bunyavirales order accommodates related viruses (bunyaviruses) with segmented, linear, single-stranded, negative- or ambi-sense RNA genomes. Their glycoproteins form capsomeric projections or spikes on the virion surface and play a crucial role in virus entry, assembly, morphogenesis. Bunyavirus glycoproteins are encoded by a single RNA segment as a polyprotein precursor that is co- and post-translationally cleaved by host cell enzymes to yield two mature glycoproteins, Gn and Gc (or GP1 and GP2 in arenaviruses). These glycoproteins undergo extensive N-linked glycosylation and despite their cleavage, remain associated to the virion to form an integral transmembrane glycoprotein complex. This review summarizes recent advances in our understanding of the molecular biology of bunyavirus glycoproteins, including their processing, structure, and known interactions with host factors that facilitate cell entry.

Cryo-EM structure of glycoprotein C from Crimean-Congo hemorrhagic fever virus

“…Within the Bunyavirales order, most fusion proteins adopt a class II fusion fold, with the remarkable exception of arenaviruses whose GP2 is a class I fusion protein ( Hulswit et al., 2021 ). Class II fusion proteins of bunyaviruses in their postfusion conformations are homotrimers, which have been structurally studied mainly by X-ray crystallography and are limited to the families Phenuiviridae [Rift Valley fever virus (RVFV) and severe fever with thrombocytopenia syndrome virus (SFTSV)] ( Halldorsson et al., 2016 ; Guardado-Calvo et al., 2017 ) and Hantaviridae [Puumala virus (PUUV), Hantaan virus (HTNV), Andes virus (ANDV) and Maporal virus (MAPV)] ( Guardado-Calvo et al., 2016 ; Willensky et al., 2016 ; Serris et al., 2020 ).…”

“…Class II fusion proteins of bunyaviruses in their postfusion conformations are homotrimers, which have been structurally studied mainly by X-ray crystallography and are limited to the families Phenuiviridae [Rift Valley fever virus (RVFV) and severe fever with thrombocytopenia syndrome virus (SFTSV)] ( Halldorsson et al., 2016 ; Guardado-Calvo et al., 2017 ) and Hantaviridae [Puumala virus (PUUV), Hantaan virus (HTNV), Andes virus (ANDV) and Maporal virus (MAPV)] ( Guardado-Calvo et al., 2016 ; Willensky et al., 2016 ; Serris et al., 2020 ). These proteins share a common molecular architecture consisting of three characteristic β-strand-rich domains, termed I, II and III ( Kielian and Rey, 2006 ; Harrison, 2015 ; Hulswit et al., 2021 ). Domain III is connected by a “stem” region to the C-terminal-proximal transmembrane domain, which anchors the fusion protein to the viral envelope.…”

Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen

“…Hantaviruses belong to the order Bunyavirales , family Hantaviridae , and are negative-sense, single-stranded RNA viruses with a tripartite genome consisting of S (small), M (medium), and L (large) segments ( 1 , 5 ). The envelope-anchored glycoproteins, Gn and Gc, are produced by enzymatic cleavage of the glycoprotein precursor (GPC) protein encoded in the M segment and are jointly responsible for orchestrating host cell entry and fusion ( 6 – 8 ). Hantavirus infection in humans generates a strong, long-lasting humoral antibody (Ab) response with neutralizing antibody (nAb) titers detectable >20 years post-infection ( 9 , 10 ).…”

Highly adaptive Phenuiviridae with biomedical importance in multiple fields

“…The longest (L) segment of genomic RNA encodes an RNA-dependent RNA polymerase (RdRp), responsible for the replication and transcription of viral genomic RNA. RdRp of phenuiviruses also has endonuclease functions [49]. The medium (M) segment encodes a precursor polypeptide, cleaved by host signal peptidase into two envelope glycoproteins, Gn and Gc.…”

“…Gn and Gc are responsible for virion binding to the target cells and penetrating the cytosol, assembling in cytosols, and they constitute tropism restriction factors. They are also the targets for neutralizing antibodies, making them key targets for vaccine development [49]. Both Gn and Gc contain Nglycosylation sites [50].…”