Long-lived Signal Peptide of Lymphocytic Choriomeningitis Virus Glycoprotein pGP-C

Froeschke, Marc; Basler, Michael; Groettrup, Marcus; Dobberstein, Bernhard

doi:10.1074/jbc.m302343200

Cited by 76 publications

(94 citation statements)

References 47 publications

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“…We used LyUV treatment of the ADC because it fully inactivated the virus and allowed for efficient NP396 crosspresentation similar to HEK-NP cells [7,8]. We initially expected that GP33 would fail to cross-present because it is located in the signal peptide of LCMV-GP [12], but it was cross-presented with low efficiency, probably due to its exceptional long half-life of 6 h [15]. Although NP396, located in the long-lived nucleoprotein [21], was efficient at cross-presentation, NP205 was poor, possibly due to inefficient processing by the phagosomal/proteasomal machineries.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, it appears that the capacity of an epitope to access cross-priming may support its immunodominance when considering the overall hierarchy [8,10,14]. Collectively, these findings seem to conflict with the immunodominant status of GP33 because this epitope is located in the signal sequence of the glycoprotein (lymphocytic choriomeningitis virus (LCMV)-GP) [15] and may not be able to cross-prime CTL [12].…”

Section: Introductionmentioning

confidence: 99%

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The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

et al. 2010

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The initiation of CD8 1 T cell (CTL) immune responses can occur via cross-priming. Recent data suggested a relationship between cross-presentation and immunodominance of epitope-specific T cells. To test this association, we evaluated the efficacy of crosspresentation for several virus epitopes in vitro and examined if this can be extrapolated in vivo. Employing lymphocytic choriomeningitis virus (LCMV), we demonstrate that the cross-presentation and cross-priming of LCMV antigens were dominated by NP396, but not NP205 when analyzing the LCMV-NP. Although with LCMV-GP, cross-presentation was dominated by GP276, and cross-priming was dominated by GP33. Importantly, although NP396 was significantly more efficient than GP33 in cross-presentation, cross-priming of their specific CTL was comparable. In a subsequent virus challenge after cross-priming, GP33-specific CTL dominated the response. Accordingly, based on our data, the ability of viral epitopes to be cross-presented in vitro does not entirely reflect what would occur in cross-priming. Thus, weak cross-presenting antigens may still cross-prime an efficient CTL response depending on other in vivo elements such as the naïve T-cell precursor frequencies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

et al. 2010

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“…The latter one includes the prototypic family members lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV) [1]. The glycoprotein of LASV is synthesized as the precursor molecule preGP-C which is co-translationally processed by the cellular signal peptidase resulting in the 6 kDa stable signal peptide (SSP) and the immature 76 kDa GP-C. Uncommonly, after cleavage the SSP stays connected to the glycoprotein complex [2][3][4]. During the transport along the secretory pathway to the plasma membrane, GP-C is then further proteolytically activated by maturation cleavage into the distal glycoprotein subunit (GP-1) (44 kDa) and the transmembrane-spanning subunit (GP-2) (36 kDa) by the cellular endoprotease subtilase subtilisin kexin isozyme-1/site 1 protease (SKI-1/S1P) [5,6].…”

Section: Introductionmentioning

confidence: 99%

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

2010

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a b s t r a c tThe Lassa virus glycoprotein consists of an ectodomain, a transmembrane anchor, and a cytoplasmic domain. It is synthesized as an inactive precursor and cleaved within the ectodomain to yield the mature form. Here, we show that this maturation cleavage can be abolished by mutation of single conserved amino acids within the cytoplasmic domain at the carboxy-terminus of the glycoprotein. Moreover, substitutions and deletions of multiple amino acids result in destabilization of the glycoprotein oligomers. These results indicate that conformation changes in the cytoplasmic domain travel across the membrane and subsequently abolish the maturation cleavage. Therefore, we postulate that the cytoplasmic domain is an important maturation factor stabilizing the overall conformation of the glycoprotein. Structured summary:MINT-7997004: LASV GP (uniprotkb:P08669) and LASV GP (uniprotkb:P08669) physically interact (MI:0915) by cosedimentation through density gradient (MI:0029)

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“…Typical SPs range in size from 15 to 25 amino acids and contain a hydrophobic core of approximately seven residues, a polar C terminus of approximately five residues, and a net positive N terminus of variable length (24). Notably, the highly conserved SSPs of LCMV and LASV contain 58 amino acids (11,16), which is unusually long for a canonical SP. Arenavirus SSPs contain a conserved Nterminal myristoyl moiety acceptance site (G2), an N-terminal extension, two hydrophobic domains (H1 [residues 10 to 32] and H2 [residues 34 to 53]) separated by a single positive charge (K33), and a C-terminal SP cleavage site (residues 54 to 58).…”

mentioning

confidence: 99%

Mapping the Landscape of the Lymphocytic Choriomeningitis Virus Stable Signal Peptide Reveals Novel Functional Domains

Saunders

Ting

Meisner

et al. 2007

J Virol

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The stable signal peptide (SSP) of the lymphocytic choriomeningitis virus surface glycoprotein precursor has several unique characteristics. The SSP is unusually long, at 58 amino acids, and contains two hydrophobic domains, and its sequence is highly conserved among both Old and New World arenaviruses. To better understand the functions of the SSP, a panel of point and deletion mutants was created by in vitro mutagenesis to target the highly conserved elements within the SSP. We were also able to confirm critical residues required for separate SSP functions by trans-complementation. Using these approaches, it was possible to resolve functional domains of the SSP. In characterizing our SSP mutants, we discovered that the SSP is involved in several distinct functions within the viral life cycle, beyond translocation of the viral surface glycoprotein precursor into the endoplasmic reticulum lumen. The SSP is required for efficient glycoprotein expression, posttranslational maturation cleavage of GP1 and GP2 by SKI-1/S1P protease, glycoprotein transport to the cell surface plasma membrane, formation of infectious virus particles, and acid pH-dependent glycoproteinmediated cell fusion.The Arenaviridae comprise a group of enveloped RNA viruses that include several causative agents of hemorrhagic fevers in the New World and Africa. Among these are Lassa fever virus (LASV) and Junín virus (JUNV). The prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), has a bisegmented, single-stranded, negative-sense RNA genome. Each of the two segments uses an ambisense coding strategy to direct the synthesis of two polypeptides. The large (L) segment (7.2 kb) encodes a small RING finger protein, Z, and the RNA-dependent RNA polymerase, the L protein, while the small (S) segment (3.4 kb) encodes the nucleoprotein, NP, and the glycoprotein (GP) precursor pGPC (5). The 498-aminoacid pGPC of LCMV consists of three domains (Fig. 1A) that are produced as independent polypeptides by posttranslational processing: residues 1 to 58 comprise the stable signal peptide (SSP), which is cotranslationally cleaved by signal peptidase and followed by the GP precursor GPC (residues 59 to 498), which is further processed into GP1 (residues 59 to 265) and GP2 (residues 266 to 498) (5, 7, 26) by the cellular protease, SKI-1/S1P (3). GP1 is heavily glycosylated, contains the receptor binding site and antibody neutralization sites, and is noncovalently associated with GP2. GP2 contains a transmembrane region and anchors the GP complex in the lipid bilayer of the cell membrane and virus envelope (6). LCMV cell entry involves a fusion event that requires exposure to acidic pH (9) to trigger GP1 dissociation from GP2 and to induce irreversible conformational changes in GP2 that mediate membrane fusion (10).Signal peptides (SPs) mediate protein translocation into the lumen of the endoplasmic reticulum (ER), promoting proper folding and posttranslational modifications of these polypeptides. Following translocation, an SP is typically cleaved and r...

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Long-lived Signal Peptide of Lymphocytic Choriomeningitis Virus Glycoprotein pGP-C

Cited by 76 publications

References 47 publications

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

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

Mapping the Landscape of the Lymphocytic Choriomeningitis Virus Stable Signal Peptide Reveals Novel Functional Domains

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