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Protein-Protein Interactions of Viroporins in Coronaviruses and Paramyxoviruses: New Targets for Antivirals?

Torres J, Surya W, Li Y, Liu DX - Viruses (2015)

Bottom Line: The channel activity and structure of some representative members of these viroporins have been recently characterized in some detail.In addition, searches for protein-protein interactions using yeast-two hybrid techniques have shed light on possible functional roles for their exposed cytoplasmic domains.These should complement current efforts to block viroporin channel activity.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore. jtorres@ntu.edu.sg.

ABSTRACT
Viroporins are members of a rapidly growing family of channel-forming small polypeptides found in viruses. The present review will be focused on recent structural and protein-protein interaction information involving two viroporins found in enveloped viruses that target the respiratory tract; (i) the envelope protein in coronaviruses and (ii) the small hydrophobic protein in paramyxoviruses. Deletion of these two viroporins leads to viral attenuation in vivo, whereas data from cell culture shows involvement in the regulation of stress and inflammation. The channel activity and structure of some representative members of these viroporins have been recently characterized in some detail. In addition, searches for protein-protein interactions using yeast-two hybrid techniques have shed light on possible functional roles for their exposed cytoplasmic domains. A deeper analysis of these interactions should not only provide a more complete overview of the multiple functions of these viroporins, but also suggest novel strategies that target protein-protein interactions as much needed antivirals. These should complement current efforts to block viroporin channel activity.

No MeSH data available.


Related in: MedlinePlus

Schematic depicting a hypothetical model for apoptosis delay through interaction of SH and BAP31 proteins. (a) Activation of caspase 8 via TNF-α or other effectors cleaves the cytoplasmic vDED domain of BAP31, producing pro-apoptotic p20; (b) SH protein may bind to various proteins in this pathway, e.g., BAP31, blocking its cleavage by caspase-8; (c) ion channel activity through SH protein may contribute to production of IL-1β through activation of the inflammasome.
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viruses-07-02750-f006: Schematic depicting a hypothetical model for apoptosis delay through interaction of SH and BAP31 proteins. (a) Activation of caspase 8 via TNF-α or other effectors cleaves the cytoplasmic vDED domain of BAP31, producing pro-apoptotic p20; (b) SH protein may bind to various proteins in this pathway, e.g., BAP31, blocking its cleavage by caspase-8; (c) ion channel activity through SH protein may contribute to production of IL-1β through activation of the inflammasome.

Mentions: Recently, a membrane-based yeast two-hybrid system (MbY2H) was used to identify a cellular binding partner of hRSV SH protein, the B-Cell receptor-associated protein 31 (BAP31) [160], in a human lung cDNA library. BAP31 is a membrane protein located at the endoplasmic reticulum (ER) and has an essential role in sorting newly synthesized membrane proteins [161]. Additionally, BAP31 has a cytoplasmic C-terminus that form two coiled coils [162,163], one of them containing a variant of the death effector domain (vDED) [164] flanked by two caspase-8 cleavage sites. This domain is excised upon activation of caspase-8 [165,166] to produce a fragment p20, known to function as a proapoptotic factor [166,167]. BAP31 also forms a complex with the mitochondrial fission 1 (Fis1) [168] membrane protein, which spans the ER and mitochondria, and serves as a platform for activation of caspase-8. The consequences, or biological relevance, of the interaction between SH and BAP31 proteins are not known. These contacts may interfere between BAP31 and caspase-8 interaction, e.g., by SH protein binding to BAP31 vDED domain. This could in turn prevent the cleavage of BAP31 and the formation of pro-apoptotic p20, thus delaying apoptosis (Figure 6).


Protein-Protein Interactions of Viroporins in Coronaviruses and Paramyxoviruses: New Targets for Antivirals?

Torres J, Surya W, Li Y, Liu DX - Viruses (2015)

Schematic depicting a hypothetical model for apoptosis delay through interaction of SH and BAP31 proteins. (a) Activation of caspase 8 via TNF-α or other effectors cleaves the cytoplasmic vDED domain of BAP31, producing pro-apoptotic p20; (b) SH protein may bind to various proteins in this pathway, e.g., BAP31, blocking its cleavage by caspase-8; (c) ion channel activity through SH protein may contribute to production of IL-1β through activation of the inflammasome.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488717&req=5

viruses-07-02750-f006: Schematic depicting a hypothetical model for apoptosis delay through interaction of SH and BAP31 proteins. (a) Activation of caspase 8 via TNF-α or other effectors cleaves the cytoplasmic vDED domain of BAP31, producing pro-apoptotic p20; (b) SH protein may bind to various proteins in this pathway, e.g., BAP31, blocking its cleavage by caspase-8; (c) ion channel activity through SH protein may contribute to production of IL-1β through activation of the inflammasome.
Mentions: Recently, a membrane-based yeast two-hybrid system (MbY2H) was used to identify a cellular binding partner of hRSV SH protein, the B-Cell receptor-associated protein 31 (BAP31) [160], in a human lung cDNA library. BAP31 is a membrane protein located at the endoplasmic reticulum (ER) and has an essential role in sorting newly synthesized membrane proteins [161]. Additionally, BAP31 has a cytoplasmic C-terminus that form two coiled coils [162,163], one of them containing a variant of the death effector domain (vDED) [164] flanked by two caspase-8 cleavage sites. This domain is excised upon activation of caspase-8 [165,166] to produce a fragment p20, known to function as a proapoptotic factor [166,167]. BAP31 also forms a complex with the mitochondrial fission 1 (Fis1) [168] membrane protein, which spans the ER and mitochondria, and serves as a platform for activation of caspase-8. The consequences, or biological relevance, of the interaction between SH and BAP31 proteins are not known. These contacts may interfere between BAP31 and caspase-8 interaction, e.g., by SH protein binding to BAP31 vDED domain. This could in turn prevent the cleavage of BAP31 and the formation of pro-apoptotic p20, thus delaying apoptosis (Figure 6).

Bottom Line: The channel activity and structure of some representative members of these viroporins have been recently characterized in some detail.In addition, searches for protein-protein interactions using yeast-two hybrid techniques have shed light on possible functional roles for their exposed cytoplasmic domains.These should complement current efforts to block viroporin channel activity.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore. jtorres@ntu.edu.sg.

ABSTRACT
Viroporins are members of a rapidly growing family of channel-forming small polypeptides found in viruses. The present review will be focused on recent structural and protein-protein interaction information involving two viroporins found in enveloped viruses that target the respiratory tract; (i) the envelope protein in coronaviruses and (ii) the small hydrophobic protein in paramyxoviruses. Deletion of these two viroporins leads to viral attenuation in vivo, whereas data from cell culture shows involvement in the regulation of stress and inflammation. The channel activity and structure of some representative members of these viroporins have been recently characterized in some detail. In addition, searches for protein-protein interactions using yeast-two hybrid techniques have shed light on possible functional roles for their exposed cytoplasmic domains. A deeper analysis of these interactions should not only provide a more complete overview of the multiple functions of these viroporins, but also suggest novel strategies that target protein-protein interactions as much needed antivirals. These should complement current efforts to block viroporin channel activity.

No MeSH data available.


Related in: MedlinePlus