Maturation cleavage within the ectodomain of Lassa virus glycoprotein relies on stabilization by the cytoplasmic tail

Schlie, Katrin; Strecker, Thomas; Garten, Wolfgang

doi:10.1016/j.febslet.2010.09.032

Cited by 18 publications

(19 citation statements)

References 22 publications

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“…Despite GP-2 being key for SSP/Z interaction (6) and GPC processing (32), only very recently, a GP-2 mutation was shown to be responsible for the in vivo attenuation of an arenavirus member, namely, the Junin virus vaccine strain Candid1 (38). Here, for the first time we demonstrate the importance of the GP-2 cytosolic tail in the viral fitness of engineered recombinant LCMV viruses expressing the LASV GP.…”

Section: Discussionmentioning

confidence: 68%

“…The LASV GPC K461G mutation is located 30 residues away from the C terminus. Alteration of the GP-2 cytosolic tail is known to have drastic effects on GPC maturation (27,32). To investigate the role of the K461G mutation on LASV mut GPC expression and processing, we transiently transfected the LASV mut GP into either SKI-1/S1P-deficient SRD12B cells or the parental cell line CHO K1.…”

Section: Rlcmv/vgks -Lcmv Gpmentioning

confidence: 99%

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Evolution of Recombinant Lymphocytic Choriomeningitis Virus/Lassa Virus In Vivo Highlights the Importance of the GPC Cytosolic Tail in Viral Fitness

Sommerstein¹,

Palma

Ölschläger

et al. 2014

J Virol

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A key characteristic of arenaviruses is their ability to establish persistent infection in their natural host. Different factors like host age, viral dose strain, and route of infection may contribute to the establishment of persistence. However, the molecular mechanisms governing persistence are not fully understood. Here, we describe gain-of-function mutations of lymphocytic choriomeningitis virus (LCMV) expressing Lassa virus (LASV) GP, which can prolong viremia in mice depending on the sequences in the GP-2 cytoplasmic tail. The initial mutant variant (rLCMV/LASV mut GP) carried a point mutation in the cytosolic tail of the LASV glycoprotein GP corresponding to a K461G substitution. Unlike what occurred with the original rLCMV/LASV wild-type (wt) GP, infection of C57BL/6 mice with the mutated recombinant virus led to a detectable viremia of 2 weeks' duration. Further replacement of the entire sequence of the cytosolic tail from LASV to LCMV GP resulted in increased viral titers and delayed clearance of the viruses. Biosynthesis and cell surface localization of LASV wt and mut GPs were comparable. IMPORTANCEStarting from an emerging virus in a wild-type mouse, we engineered a panel of chimeric Lassa/lymphocytic choriomeningitis viruses. Mutants carrying a viral envelope with the cytosolic tail from the closely related mouse-adapted LCMV were able to achieve a productive viral infection lasting up to 27 days in wild-type mice. Biochemical assays showed a comparable biosynthesis and cell surface localization of LASV wt and mut GPs. These recombinant chimeric viruses could allow the study of immune responses and antivirals targeting the LASV GP.T he prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) represents a powerful experimental model used to study the virus-host interaction of noncytopathic viruses and the role of T cells in clearing viral infections in mouse models (1). Infection with several existing strains results in different outcomes causing either transient, acute infection with virus-specific protective immunity or protracted, chronic infection with persisting viremia and immunosuppression (2). LCMV is an enveloped virus comprising two segments (S and L) of ambisense singlestranded RNA. The S RNA encodes the nucleoprotein (NP) and the envelope glycoprotein precursor (GPC) that is posttranslationally cleaved by signal peptidase and the cellular proprotein convertase SKI-1/S1P into the mature virion glycoprotein complex SSP/GP-1/GP-2 (GPs). The L RNA encodes the RNA-dependent RNA polymerase (L) and a small RING finger protein (Z). The GP mediates cell target attachment and fusion. NP and Z cover several functions, including inhibition of the innate immune response and viral particle budding, respectively. NP and L assemble with the two ambisense segments to form the ribonucleoprotein complexes (RNPs), which serve as the templates for transcription and replication. It has been shown that in LCMV the viral polymerase L and GP-1 of the glycoprotein are important determinants for the...

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Section: Discussionmentioning

confidence: 68%

Section: Rlcmv/vgks -Lcmv Gpmentioning

confidence: 99%

Evolution of Recombinant Lymphocytic Choriomeningitis Virus/Lassa Virus In Vivo Highlights the Importance of the GPC Cytosolic Tail in Viral Fitness

Sommerstein¹,

Palma

Ölschläger

et al. 2014

J Virol

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“…In a very recent report, Schlie et al (44) have shown that the exchange of the LASV GPC CT with that of the closely related LCMV also blocked SKI-1/S1P cleavage. The exact reason for the block remains unclear, but current data suggest that the chimeric GPC was not in the correct ternary or quaternary conformation to allow SKI-1/S1P cleavage.…”

Section: Discussionmentioning

confidence: 96%

“…Schlie et al (44) have recently described the relationship of LASV CT to GPC maturation. That report suggested that LASV CT was required for correct GPC oligomerization, which seemed to be a prerequisite for SKI-1/S1P processing.…”

Section: Discussionmentioning

confidence: 99%

“…The correct interaction between SSP and CT apparently triggers a change in conformation of the GPC into a trimer that is selectively cleaved; thus, processing of SKI-1 appears to serve a quality control step where only trimers are incorporated in virions. Without proper oligomerization and interactions of the SSP and G2, an uncleaved form of GPC can be found on the cellular plasma membrane; however, this immature glycoprotein precursor is unable to form infectious virus particles (2,27,44).…”

Section: Discussionmentioning

confidence: 99%

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Reverse Genetics Generation of Chimeric Infectious Junin/Lassa Virus Is Dependent on Interaction of Homologous Glycoprotein Stable Signal Peptide and G2 Cytoplasmic Domains

Albariño

Bird

Chakrabarti

et al. 2011

J Virol

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The Arenaviridae are a diverse and globally distributed collection of viruses that are maintained primarily by rodent reservoirs. Junin virus (JUNV) and Lassa virus (LASV) can both cause significant outbreaks of severe and often fatal human disease throughout their respective areas of endemicity. In an effort to improve upon the existing live attenuated JUNV Candid1 vaccine, we generated a genetically homogenous stock of this virus from cDNA copies of the virus S and L segments by using a reverse genetics system. Further, these cDNAs were used in combination with LASV cDNAs to successfully generate two recombinant Candid1 JUNV/LASV chimeric viruses (via envelope glycoprotein [GPC] exchange). It was found that while the GPC extravirion domains were readily exchangeable, homologous stable signal peptide (SSP) and G2 transmembrane and cytoplasmic tail domains were essential for correct GPC maturation and production of infectious chimeric viruses. The switching of the JUNV and LASV G1/G2 ectodomains within the Candid1 vaccine background did not alter the attenuated phenotype of the vaccine strain in a lethal mouse model. These recombinant chimeric viruses shed light on the fundamental requirements of arenavirus GPC maturation and may serve as a strategy for the development of bivalent JUNV and LASV vaccine candidates.

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Cleavage of the Glycoprotein of Arenaviruses

Pasquato

Cendron

Kunz

2018

Activation of Viruses by Host Proteases

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Maturation cleavage within the ectodomain of Lassa virus glycoprotein relies on stabilization by the cytoplasmic tail

Cited by 18 publications

References 22 publications

Evolution of Recombinant Lymphocytic Choriomeningitis Virus/Lassa Virus In Vivo Highlights the Importance of the GPC Cytosolic Tail in Viral Fitness

Evolution of Recombinant Lymphocytic Choriomeningitis Virus/Lassa Virus In Vivo Highlights the Importance of the GPC Cytosolic Tail in Viral Fitness

Reverse Genetics Generation of Chimeric Infectious Junin/Lassa Virus Is Dependent on Interaction of Homologous Glycoprotein Stable Signal Peptide and G2 Cytoplasmic Domains

Cleavage of the Glycoprotein of Arenaviruses

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