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Sedimentation Equilibrium of a Small Oligomer-forming Membrane Protein: Effect of Histidine Protonation on Pentameric Stability
Published on: April 2, 2015
Function of small hydrophobic proteins of paramyxovirus
Rebecca L Wilson1, Sandra M Fuentes, Ping Wang
1Center of Molecular Immunology and Infectious Disease, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, 115 Henning Bldg., University Park, PA 16802, USA.
Abstract:
Mumps virus (MuV), a rubulavirus of the paramyxovirus family, causes acute infections in humans. MuV has seven genes including a small hydrophobic (SH) gene, which encodes a type I membrane protein of 57 amino acid residues. The function of the SH protein is not clear, although its expression is not necessary for growth of MuV in tissue culture cells. It is speculated that MuV SH plays a role in viral pathogenesis. Simian virus 5 (SV5), a closely related rubulavirus, encodes a 44-amino-acid-residue SH protein. Recombinant SV5 lacking the SH gene (rSV5DeltaSH) is viable and has no growth defect in tissue culture cells. However, rSV5DeltaSH induces apoptosis in tissue culture cells and is attenuated in vivo. Neutralizing antibodies against tumor necrosis factor alpha (TNF-alpha) and TNF-alpha receptor 1 block rSV5DeltaSH-induced apoptosis, suggesting that SV5 SH plays an essential role in blocking the TNF-alpha-mediated apoptosis pathway. Because MuV is closely related to SV5, we hypothesize that the SH protein of MuV has a function similar to that of SV5, even though there is no sequence homology between them. To test this hypothesis and to study the function of MuV SH, we have replaced the open reading frame (ORF) of SV5 SH with the ORF of MuV SH in a SV5 genome background. The recombinant SV5 (rSV5DeltaSH+MuV-SH) was analyzed in comparison with SV5. It was found that rSV5DeltaSH+MuV-SH was viable and behaved like wild-type SV5, suggesting that MuV SH has a function similar to that of SV5 SH. Furthermore, both ectopically expressed SV5 SH and MuV SH blocked activation of NF-kappaB by TNF-alpha in a reporter gene assay, suggesting that both SH proteins can inhibit TNF-alpha signaling.
Insights
The small hydrophobic (SH) protein of mumps virus (MuV) can inhibit tumor necrosis factor alpha (TNF-alpha) signaling, similar to its counterpart in Simian virus 5 (SV5). This suggests a conserved role for SH proteins in viral pathogenesis and immune evasion.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Mumps virus (MuV) and Simian virus 5 (SV5) are related rubulaviruses.
- The function of MuV small hydrophobic (SH) protein is unknown, but SV5 SH is implicated in blocking TNF-alpha-mediated apoptosis.
- SV5 lacking SH is attenuated and induces apoptosis, highlighting SH's role in pathogenesis.
Purpose of the Study:
- To investigate the function of the MuV SH protein.
- To determine if MuV SH shares functional similarities with SV5 SH.
- To explore the role of MuV SH in viral pathogenesis and immune modulation.
Main Methods:
- Construction of a recombinant SV5 genome with the MuV SH open reading frame (ORF).
- Analysis of recombinant virus (rSV5DeltaSH+MuV-SH) viability and growth compared to wild-type SV5.
- Reporter gene assays to assess the effect of MuV SH and SV5 SH on TNF-alpha-induced NF-kappaB activation.
Main Results:
- Recombinant SV5 expressing MuV SH (rSV5DeltaSH+MuV-SH) was viable and behaved like wild-type SV5.
- MuV SH, like SV5 SH, inhibited TNF-alpha-induced activation of NF-kappaB.
- These findings suggest a conserved function for SH proteins in inhibiting TNF-alpha signaling.
Conclusions:
- The MuV SH protein possesses a function analogous to SV5 SH.
- MuV SH likely plays a role in viral pathogenesis by modulating host immune responses, specifically TNF-alpha signaling.
- This study provides insights into the conserved mechanisms of paramyxovirus immune evasion.
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