Nucleozin Targets Cytoplasmic Trafficking of Viral Ribonucleoprotein-Rab11 Complexes in Influenza A Virus Infection

被引:48
作者
Amorim, Maria Joao [1 ,2 ]
Kao, Richard Y. [3 ,4 ]
Digard, Paul [1 ,5 ]
机构
[1] Univ Cambridge, Dept Pathol, Div Virol, Cambridge CB2 1QP, England
[2] Inst Gulbenkian Ciencias, Oeiras, Portugal
[3] Univ Hong Kong, LKS Fac Med, Dept Microbiol, Hong Kong, Hong Kong, Peoples R China
[4] Univ Hong Kong, LKS Fac Med, Res Ctr Infect & Immunol, Hong Kong, Hong Kong, Peoples R China
[5] Univ Edinburgh, Roslin Inst, Easter Bush, Midlothian, Scotland
基金
英国生物技术与生命科学研究理事会;
关键词
MATRIX PROTEIN; NP-BINDING; IN-VITRO; IDENTIFICATION; NUCLEOPROTEIN; GENOME; TRANSPORT; REPLICATION; INHIBITION; MECHANISM;
D O I
10.1128/JVI.03123-12
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Novel antivirals are needed to supplement existing control strategies for influenza A virus (IAV). A promising new class of drug, exemplified by the compound nucleozin, has recently been identified that targets the viral nucleoprotein (NP). These inhibitors are thought to act as "molecular staples" that stabilize interactions between NP monomers, promoting the formation of nonfunctional aggregates. Here we detail the inhibitory mechanism of nucleozin, finding that the drug has both early-and late-acting effects on the IAV life cycle. When present at the start of infection, it inhibited viral RNA and protein synthesis. However, when added at later time points, it still potently blocked the production of infectious progeny but without affecting viral macromolecular synthesis. Instead, nucleozin blocked the cytoplasmic trafficking of ribonucleoproteins (RNPs) that had undergone nuclear export, promoting the formation of large perinuclear aggregates of RNPs along with cellular Rab11. This effect led to the production of much reduced amounts of often markedly smaller virus particles. We conclude that the primary target of nucleozin is the viral RNP, not NP, and this work also provides proof of the principle that IAV replication can be effectively inhibited by blocking cytoplasmic trafficking of the viral genome.
引用
收藏
页码:4694 / 4703
页数:10
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