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Published on: March 2, 2016
Biological roles and functional mechanisms of arenavirus Z protein in viral replication
Jialong Wang1, Shamika Danzy, Naveen Kumar
1Department of Veterinary and Biomedical Sciences, University of Minnesota, Twin Cities, Minnesota, USA.
Abstract:
Arenaviruses can cause severe hemorrhagic fever diseases in humans, with limited prophylactic or therapeutic measures. A small RING-domain viral protein Z has been shown to mediate the formation of virus-like particles and to inhibit viral RNA synthesis, although its biological roles in an infectious viral life cycle have not been directly addressed. By taking advantage of the available reverse genetics system for a model arenavirus, Pichinde virus (PICV), we provide the direct evidence for the essential biological roles of the Z protein's conserved residues, including the G2 myristylation site, the conserved C and H residues of RING domain, and the poorly characterized C-terminal L79 and P80 residues. Dicodon substitutions within the late (L) domain (PSAPPYEP) of the PICV Z protein, although producing viable mutant viruses, have significantly reduced virus growth, a finding suggestive of an important role for the intact L domain in viral replication. Further structure-function analyses of both PICV and Lassa fever virus Z proteins suggest that arenavirus Z proteins have similar molecular mechanisms in mediating their multiple functions, with some interesting variations, such as the role of the G2 residue in blocking viral RNA synthesis. In summary, our studies have characterized the biological roles of the Z protein in an infectious arenavirus system and have shed important light on the distinct functions of its domains in virus budding and viral RNA regulation, the knowledge of which may lead to the development of novel antiviral drugs.
Insights
The Pichinde virus Z protein is essential for arenavirus replication and viral RNA regulation. Understanding its functions offers potential for developing new antiviral therapies against hemorrhagic fever viruses.
Area of Science:
- Virology
- Molecular Biology
- Infectious Diseases
Background:
- Arenaviruses cause severe human hemorrhagic fevers with few treatment options.
- The viral protein Z is implicated in virus-like particle formation and RNA synthesis inhibition.
- Its precise roles in the infectious viral life cycle remain largely uncharacterized.
Purpose of the Study:
- To elucidate the essential biological roles of the Pichinde virus (PICV) Z protein during an infectious viral life cycle.
- To investigate the functions of conserved residues within the Z protein, including the G2 myristylation site, RING domain, and C-terminal residues.
- To explore the significance of the Z protein's late (L) domain in viral replication and budding.
Main Methods:
- Utilized a reverse genetics system for Pichinde virus (PICV).
- Introduced dicodon substitutions in the Z protein's late (L) domain.
- Performed structure-function analyses on PICV and Lassa fever virus Z proteins.
Main Results:
- Demonstrated essential roles for conserved Z protein residues (G2, RING domain C/H, L79/P80) in viral replication.
- Showed that dicodon substitutions in the L domain significantly reduced virus growth, highlighting its importance.
- Identified conserved molecular mechanisms and variations (e.g., G2 residue function) in Z protein activity across different arenaviruses.
Conclusions:
- Characterized the critical biological functions of the arenavirus Z protein in an infectious context.
- Elucidated the distinct roles of Z protein domains in virus budding and viral RNA regulation.
- Provided insights that may facilitate the development of novel antiviral strategies against arenavirus infections.
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