Dephosphorylation of HuR Protein during Alphavirus Infection Is Associated with HuR Relocalization to the Cytoplasm

Dickson, Alexa; Anderson, John R.; Barnhart, Michael D.; Sokoloski, Kevin J.; Oko, Lauren; Opyrchal, Mateusz; Galanis, Evanthia; Wilusz, Carol J.; Morrison, Thomas E.; Wilusz, Jeffrey

doi:10.1074/jbc.m112.371203

Cited by 52 publications

(59 citation statements)

References 40 publications

(53 reference statements)

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“…HuR relocalization has been observed upon infection with alphaviruses but not dengue virus which, like HCV, belongs to the Flaviviridae family (46). Hence, it may not be a general phenomenon observed in all members of the Flaviviridae family.…”

Section: Discussionmentioning

confidence: 95%

HuR Displaces Polypyrimidine Tract Binding Protein To Facilitate La Binding to the 3′ Untranslated Region and Enhances Hepatitis C Virus Replication

Shwetha

Kumar

Mullick

et al. 2015

J Virol

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HuR is a ubiquitous, RNA binding protein that influences the stability and translation of several cellular mRNAs. Here, we report a novel role for HuR, as a regulator of proteins assembling at the 3= untranslated region (UTR) of viral RNA in the context of hepatitis C virus (HCV) infection. HuR relocalizes from the nucleus to the cytoplasm upon HCV infection, interacts with the viral polymerase (NS5B), and gets redistributed into compartments of viral RNA synthesis. Depletion in HuR levels leads to a significant reduction in viral RNA synthesis. We further demonstrate that the interaction of HuR with the 3= UTR of the viral RNA affects the interaction of two host proteins, La and polypyrimidine tract binding protein (PTB), at this site. HuR interacts with La and facilitates La binding to the 3= UTR, enhancing La-mediated circularization of the HCV genome and thus viral replication. In addition, it competes with PTB for association with the 3= UTR, which might stimulate viral replication. Results suggest that HuR influences the formation of a cellular/viral ribonucleoprotein complex, which is important for efficient initiation of viral RNA replication. Our study unravels a novel strategy of regulation of HCV replication through an interplay of host and viral proteins, orchestrated by HuR. IMPORTANCE Hepatitis C virus (HCV) is highly dependent on various host factors for efficient replication of the viral RNA.Here, we have shown how a host factor (HuR) migrates from the nucleus to the cytoplasm and gets recruited in the protein complex assembling at the 3= untranslated region (UTR) of HCV RNA. At the 3= UTR, it facilitates circularization of the viral genome through interaction with another host factor, La, which is critical for replication. Also, it competes with the host protein PTB, which is a negative regulator of viral replication. Results demonstrate a unique strategy of regulation of HCV replication by a host protein through alteration of its subcellular localization and interacting partners. The study has advanced our knowledge of the molecular mechanism of HCV replication and unraveled the complex interplay between the host factors and viral RNA that could be targeted for therapeutic interventions. Hepatitis C virus (HCV) was discovered in 1989 as a major cause of chronic non-A non-B hepatitis (1). HCV is an enveloped positive-strand RNA virus classified in the Hepacivirus genus within the Flaviviridae family. The single-stranded uncapped 9.6-kb RNA codes for a long polyprotein of ϳ3,000 amino acids which is then processed to structural and nonstructural proteins. The RNA genome is flanked by the 5= and 3= untranslated regions (UTRs), which are essential for translation and replication of the viral RNA. The viral proteins are synthesized by internal ribosome entry site (IRES)-mediated translation. These proteins initiate extensive remodeling of the intracellular membranes to create a detergent-resistant scaffold for viral replication, termed as the "membranous web" (2). The progeny viral genomes a...

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Section: Discussionmentioning

confidence: 95%

HuR Displaces Polypyrimidine Tract Binding Protein To Facilitate La Binding to the 3′ Untranslated Region and Enhances Hepatitis C Virus Replication

Shwetha

Kumar

Mullick

et al. 2015

J Virol

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“…by p38, dictates their activity. Modulation of ARE interacting proteins has been noted as a mechanism by which viruses influence inflammatory responses in host cells [32,33]. …”

Section: Discussionmentioning

confidence: 99%

Virulent <b><i>Francisella tularensis</i></b> Destabilize Host mRNA to Rapidly Suppress Inflammation

Bauler¹,

Chase²,

Wehrly³

et al. 2014

J Innate Immun

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Highly virulent bacterial pathogens have evolved rapid means to suppress host inflammatory responses by unknown mechanisms. Here, we use virulent Francisella tularensis, the cause of lethal tularemia in humans, as a model to elucidate these mechanisms. We show that following infection of murine macrophages F. tularensis rapidly and selectively destabilizes mRNA containing adenylate-uridylate-rich elements that encode for cytokines and chemokines important in controlling bacterial infection. Degradation of host mRNA encoding interleukin (IL)-1β, IL-6 and CXCL1 did not require viable bacteria or de novo protein synthesis, but did require escape of intracellular organisms from endocytic vesicles into the host cytosol. The specific targeting of host mRNA encoding inflammatory cytokines and chemokines for decay by a bacterial pathogen has not been previously reported. Thus, our findings represent a novel strategy by which a highly virulent pathogen modulates host inflammatory responses critical to the evasion of innate immunity.

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“…First, the 3′UTRs in both alphaviruses [15]–[18] and flaviviruses [19] interact with cellular proteins (in both mosquito and mammalian cells) to directly or indirectly facilitate genome replication. It has been observed that several alphaviruses usurp the cellular HuR protein, which enhances mRNA stability and therefore inhibits viral RNA decay [16]–[18]. Additionally, arboviral 3′UTRs can encode microRNAs (miRNAs, such as observed in West Nile virus) which regulate cellular gene expression to enhance viral replication [20].…”

Section: Introductionmentioning

confidence: 99%

Chikungunya Virus 3′ Untranslated Region: Adaptation to Mosquitoes and a Population Bottleneck as Major Evolutionary Forces

et al. 2013

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The 3′ untranslated genome region (UTR) of arthropod-borne viruses is characterized by enriched direct repeats (DRs) and stem-loop structures. Despite many years of theoretical and experimental study, on-going positive selection on the 3′UTR had never been observed in ‘real-time,’ and the role of the arbovirus 3′UTR remains poorly understood. We observed a lineage-specific 3′UTR sequence pattern in all available Asian lineage of the mosquito-borne alphavirus, chikungunya virus (CHIKV) (1958–2009), including complicated mutation and duplication patterns of the long DRs. Given that a longer genome is usually associated with less efficient replication, we hypothesized that the fixation of these genetic changes in the Asian lineage 3′UTR was due to their beneficial effects on adaptation to vectors or hosts. Using reverse genetic methods, we examined the functional importance of each direct repeat. Our results suggest that adaptation to mosquitoes, rather than to mammalian hosts, is a major evolutionary force on the CHIKV 3′UTR. Surprisingly, the Asian 3′UTR appeared to be inferior to its predicted ancestral sequence for replication in both mammals and mosquitoes, suggesting that its fixation in Asia was not a result of directional selection. Rather, it may have resulted from a population bottleneck during its introduction from Africa to Asia. We propose that this introduction of a 3′UTR with deletions led to genetic drift and compensatory mutations associated with the loss of structural/functional constraints, followed by two independent beneficial duplications and fixation due to positive selection. Our results provide further evidence that the limited epidemic potential of the Asian CHIKV strains resulted from founder effects that reduced its fitness for efficient transmission by mosquitoes there.

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Dephosphorylation of HuR Protein during Alphavirus Infection Is Associated with HuR Relocalization to the Cytoplasm

Cited by 52 publications

References 40 publications

HuR Displaces Polypyrimidine Tract Binding Protein To Facilitate La Binding to the 3′ Untranslated Region and Enhances Hepatitis C Virus Replication

HuR Displaces Polypyrimidine Tract Binding Protein To Facilitate La Binding to the 3′ Untranslated Region and Enhances Hepatitis C Virus Replication

Virulent <b><i>Francisella tularensis</i></b> Destabilize Host mRNA to Rapidly Suppress Inflammation

Chikungunya Virus 3′ Untranslated Region: Adaptation to Mosquitoes and a Population Bottleneck as Major Evolutionary Forces

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