The cytoplasmic tail of hantavirus Gn glycoprotein interacts with RNA

Strandin, Tomas; Hepojoki, Jussi; Wang, Hao; Vaheri, Antti; Lankinen, Hilkka

doi:10.1016/j.virol.2011.06.030

Cited by 28 publications

(22 citation statements)

References 56 publications

(85 reference statements)

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“…The hantavirus glycoproteins are primed by proteolytical processing, most likely whilst being translated as glycoprotein precursor (GPC) (Löber et al, 2001). During the entry process, a role of cellular factors in glycoprotein priming by thiolisothiomerases has been previously suggested (Strandin et al, 2011). Once activated, viral fusion proteins expose an amphipathic fusion peptide that drives their insertion into the target membrane (Epand, 2003;Harter et al, 1989).…”

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confidence: 99%

Acidification triggers Andes hantavirus membrane fusion and rearrangement of Gc into a stable post-fusion homotrimer

Acuña

Bignon

Mancini

et al. 2015

Journal of General Virology

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The hantavirus membrane fusion process is mediated by the Gc envelope glycoprotein from within endosomes. However, little is known about the specific mechanism that triggers Gc fusion activation, and its pre-and post-fusion conformations. We established cell-free in vitro systems to characterize hantavirus fusion activation. Low pH was sufficient to trigger the interaction of virus-like particles with liposomes. This interaction was dependent on a pre-fusion glycoprotein arrangement. Further, low pH induced Gc multimerization changes leading to non-reversible Gc homotrimers. These trimers were resistant to detergent, heat and protease digestion, suggesting characteristics of a stable post-fusion structure. No acid-dependent oligomerization rearrangement was detected for the trypsin-sensitive Gn envelope glycoprotein. Finally, acidification induced fusion of glycoprotein-expressing effector cells with non-susceptible CHO cells. Together, the data provide novel information on the Gc fusion trigger and its non-reversible activation involving lipid interaction, multimerization changes and membrane fusion which ultimately allow hantavirus entry into cells.

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mentioning

confidence: 99%

Acidification triggers Andes hantavirus membrane fusion and rearrangement of Gc into a stable post-fusion homotrimer

Acuña

Bignon

Mancini

et al. 2015

Journal of General Virology

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“…How does the I532K mutation enhance cell surface expression of HTNV Gn/Gc? I532 is located in the region that has been shown to bind hantavirus nucleoprotein and RNA (58, 59), just upstream of the dual zinc finger domains in the cytoplasmic tail of the Gn (Gn-CT) protein ( Fig. 7 ).…”

Section: Discussionmentioning

confidence: 99%

Two point mutations in the Hantaan virus glycoproteins afford the generation of a highly infectious recombinant vesicular stomatitis virus vector

Slough

Chandran

Jangra

2018

Preprint

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wordsAbstract 24 Rodent-to-human transmission of hantaviruses is associated with severe disease. 25 Currently, no FDA-approved, specific antivirals or vaccines are available, and the requirement 26 for high biocontainment (BSL3) laboratories limits hantavirus research. To study hantavirus 27 entry in a BSL-2 laboratory, we set out to generate replication-competent, recombinant vesicular 28 stomatitis viruses (rVSVs) bearing the Gn/Gc entry glycoproteins. As previously reported, 29 rVSVs bearing New World hantavirus Gn/Gc were readily rescued from cDNAs, but their 30 counterparts bearing Gn/Gc from the Old World hantavirus, Hantaan virus (HTNV), were 31 refractory to rescue and only grew to low titers. However, serial passage of the rescued rVSV-32 HTNV Gn/Gc virus markedly increased its infectivity and capacity for cell-to-cell spread. This 33 gain in viral fitness was associated with the acquisition of two point mutations; I532K in the 34 cytoplasmic tail of Gn, and S1094L in the membrane-proximal stem of Gc. Follow-up 35 experiments with rVSVs and single-cycle VSV pseudotypes confirmed these results. 36 Mechanistic studies revealed that both mutations were determinative and contributed to viral 37 infectivity in a synergistic manner. Our findings indicate that the primary mode of action of these 38 mutations is to relocalize HTNV Gn/Gc from the Golgi complex to the cell surface, thereby 39 affording significantly enhanced Gn/Gc incorporation into budding VSV particles. Our results 40 suggest that enhancements in cell-surface expression of hantaviral glycoprotein(s) through 41 incorporation of cognate mutations could afford the generation of rVSVs that are otherwise 42 challenging to rescue. The robust replication-competent rVSV-HTNV Gn/Gc reported herein 43 may also have utility as a vaccine. 44 45 3 Importance 46 Human hantavirus infections cause pulmonary syndrome in the Americas and 47 hemorrhagic fever with renal syndrome (HFRS) in Eurasia. No FDA-approved vaccines and 48 therapeutics exist for these deadly viruses, and their development is limited by the requirement 49 for high biocontainment. In this study, we identified and characterized key amino acid changes in 50 the surface glycoproteins of HFRS-causing Hantaan virus that enhance their incorporation into 51 recombinant vesicular stomatitis virus (rVSV) particles. The replication-competent rVSV 52 genetically encoding Hantaan virus glycoproteins described in this work provides a powerful and 53 facile system to study hantavirus entry under lower biocontainment and may have utility as a 54 hantavirus vaccine.55 56 Rodent-borne hantaviruses (family Hantaviridae of segmented negative-strand RNA 57 viruses) cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus 58 pulmonary syndrome (HPS) in the Americas (1). Globally, more than 150,000 cases of 59 hantavirus disease occur per year. Human population growth, accelerating climate change, and 60habitat loss are predicted to increase the size and severity of hantavirus ...

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“…The Gn and Gc proteins are glycosylated in the RER [65] and traffic through the Golgi complex until they assemble into particles. The Gn-CT has been shown to bind to nucleic acid [66] and N protein [67]in vitro, and is suggested to act as a matrix protein [68]. At some point following mRNA transcription, the RdRp begins replication of the cRNAs and vRNAs (Figure 1e).…”

Section: Structure and Function Of Hantaviral Proteinsmentioning

confidence: 99%

Hantaviruses: Past, Present and Future

McAllister

Jonsson

2014

Future Virology

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Introduction to the discovery of hantaviruses & their diseases Historical gretrospectives of medical reports suggest that trench nephritis in the first World War, nephropathia epidemica (NE) in Scandinavia, Song-go fever in Manchuria and hemorrhagic nephrosonephritis in the Soviet Union were all potentially caused by hantaviruses [1-4]. However, it was not until Hantaan virus (HTNV) was isolated in 1977 that two human diseases were attributed to hantaviruses; hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia, and NE, a mild form of HFRS, in northern Europe. Four Hantavirus species are now recognized to cause HFRS (HTNV harbored by Apodemus agrarius [1]; Dobrava-Belgrade virus, harbored by A. agrarius, A flavicollis and A. ponticus rodents [5,6]; Seoul virus, SEOV, harbored by Rattus norvegicus [7]) and NE (Puumala virus, PUUV, harbored by Myodes glareolus). Combined, these viruses have a global public health impact estimated at over 50,000 cases each year, with lethality ranging from <1 to 12% [8]. The wide prevalence of hantaviruses in rodents in Europe and Asia suggested the potential for hantaviruses in New World rodents. In the mid-1980s rodent surveillance efforts discovered Prospect Hill virus (PHV), harbored by Microtus pennsylvanicus [9], and crossreactive antibodies were reported in Peromyscus maniculatus, P. difficilis, P. californicus, Neotoma mexicana and N. cinerea in the USA [10], and in Old World (laboratory) rodents in South America [11]. It was not long after these efforts that an outbreak of hantavirus pulmonary syndrome (HPS) in individuals residing in the Four Corners area in the southwestern USA in 1993 confirmed the presence of disease-causing hantaviruses in the Americas. In the Spring of 1993, two young, healthy adults living in the Navajo Nation fell ill and died from an unexplained acute respiratory distress syndrome (ARDS) [12]. Unexplained deaths are reported to part of

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The cytoplasmic tail of hantavirus Gn glycoprotein interacts with RNA

Cited by 28 publications

References 56 publications

Acidification triggers Andes hantavirus membrane fusion and rearrangement of Gc into a stable post-fusion homotrimer

Acidification triggers Andes hantavirus membrane fusion and rearrangement of Gc into a stable post-fusion homotrimer

Two point mutations in the Hantaan virus glycoproteins afford the generation of a highly infectious recombinant vesicular stomatitis virus vector

Hantaviruses: Past, Present and Future

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