Dengue virus NS1 protein interacts with the ribosomal protein RPL18: This interaction is required for viral translation and replication in Huh-7 cells

Cervantes-Salazar, Margot; Ángel-Ambrocio, Antonio H.; Soto-Acosta, Rubén; Bautista‐Carbajal, Patricia; Hurtado-Monzón, Arianna Mahely; Alcaráz-Estrada, Sofía Lizeth; Ludert, Juan E.; Ángel, Rosa M. del

doi:10.1016/j.virol.2015.05.017

Cited by 74 publications

(57 citation statements)

References 55 publications

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“…Second, DENV infection might limit the availability of the translation machinery components such as ribosomal subunits. Affinity purification and mass spectrometry analyses of DENV-infected cells revealed the interaction of NS1 with over 30 ribosomal proteins such as RPL18 which is required for both viral replication and translation (86). Third, our results indicate that viral replication is dispensable for the induction of translational repression, as illustrated by the absence of puromycin incorporation in single cells expressing DENV polyprotein.…”

Section: Discussionmentioning

confidence: 99%

Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses

Roth

Magg

Uch

et al. 2017

mBio

122

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As obligate parasites, viruses strictly depend on host cell translation for the production of new progeny, yet infected cells also synthesize antiviral proteins to limit virus infection. Modulation of host cell translation therefore represents a frequent strategy by which viruses optimize their replication and spread. Here we sought to define how host cell translation is regulated during infection of human cells with dengue virus (DENV) and Zika virus (ZIKV), two positive-strand RNA flaviviruses. Polysome profiling and analysis of de novo protein synthesis revealed that flavivirus infection causes potent repression of host cell translation, while synthesis of viral proteins remains efficient. Selective repression of host cell translation was mediated by the DENV polyprotein at the level of translation initiation. In addition, DENV and ZIKV infection suppressed host cell stress responses such as the formation of stress granules and phosphorylation of the translation initiation factor eIF2α (α subunit of eukaryotic initiation factor 2). Mechanistic analyses revealed that translation repression was uncoupled from the disruption of stress granule formation and eIF2α signaling. Rather, DENV infection induced p38-Mnk1 signaling that resulted in the phosphorylation of the eukaryotic translation initiation factor eIF4E and was essential for the efficient production of virus particles. Together, these results identify the uncoupling of translation suppression from the cellular stress responses as a conserved strategy by which flaviviruses ensure efficient replication in human cells.

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Section: Discussionmentioning

confidence: 99%

Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses

Roth

Magg

Uch

et al. 2017

mBio

122

View full text Add to dashboard Cite

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“…*, P Ͻ 0.05; **, P Ͻ 0.01; ***, P Ͻ 0.001; ****, P Ͻ 0.0001. DENV-2 infection without affecting global cellular translation or cell viability (52). RPS25 appears to be broadly required for IRES-mediated translation initiation of HCV, human T-cell leukemia virus 1, Cricket paralysis virus, and poliovirus, as well as ribosome shunting in adenovirus infection (21,53,54).…”

Section: Discussionmentioning

confidence: 99%

RPLP1 and RPLP2 Are Essential Flavivirus Host Factors That Promote Early Viral Protein Accumulation

Campos

Wong

Xie

et al. 2017

J Virol

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The Flavivirus genus contains several arthropod-borne viruses that pose global health threats, including dengue viruses (DENV), yellow fever virus (YFV), and Zika virus (ZIKV). In order to understand how these viruses replicate in human cells, we previously conducted genome-scale RNA interference screens to identify candidate host factors. In these screens, we identified ribosomal proteins RPLP1 and RPLP2 (RPLP1/2) to be among the most crucial putative host factors required for DENV and YFV infection. RPLP1/2 are phosphoproteins that bind the ribosome through interaction with another ribosomal protein, RPLP0, to form a structure termed the ribosomal stalk. RPLP1/2 were validated as essential host factors for DENV, YFV, and ZIKV infection in two human cell lines: A549 lung adenocarcinoma and HuH-7 hepatoma cells, and for productive DENV infection of Aedes aegypti mosquitoes. Depletion of RPLP1/2 caused moderate cell-line-specific effects on global protein synthesis, as determined by metabolic labeling. In A549 cells, global translation was increased, while in HuH-7 cells it was reduced, albeit both of these effects were modest. In contrast, RPLP1/2 knockdown strongly reduced early DENV protein accumulation, suggesting a requirement for RPLP1/2 in viral translation. Furthermore, knockdown of RPLP1/2 reduced levels of DENV structural proteins expressed from an exogenous transgene. We postulate that these ribosomal proteins are required for efficient translation elongation through the viral open reading frame. In summary, this work identifies RPLP1/2 as critical flaviviral host factors required for translation.IMPORTANCE Flaviviruses cause important diseases in humans. Examples of mosquito-transmitted flaviviruses include dengue, yellow fever and Zika viruses. Viruses require a plethora of cellular factors to infect cells, and the ribosome plays an essential role in all viral infections. The ribosome is a complex macromolecular machine composed of RNA and proteins and it is responsible for protein synthesis. We identified two specific ribosomal proteins that are strictly required for flavivirus infection of human cells and mosquitoes: RPLP1 and RPLP2 (RPLP1/2). These proteins are part of a structure known as the ribosomal stalk and help orchestrate the elongation phase of translation. We show that flaviviruses are particularly dependent on the function of RPLP1/2. Our findings suggest that ribosome composition is an important factor for virus translation and may represent a regulatory layer for translation of specific cellular mRNAs. (1)(2)(3)(4). Dengue viruses (DENV-1 to -4), the most prevalent of all arthropod-borne viruses, infect approximately 390 million people per year (1); yellow fever virus (YFV), which causes life-threatening disease (5) has reemerged this year in Africa (6); Zika virus (ZIKV) is currently responsible for a pandemic in the Americas that has caused grave concern because of associations with birth defects and Guillain-Barré syndrome (3). KEYWORDS flavivirus, ribosomal proteins, tran...

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“…It is demonstrated that N of Rice stripe tenuivirus interacts with RPL18 of insect vector and silencing of RPL18 significantly reduces viral translation and replication in insect vector [82]. Interaction between NS1 of Dengue virus (DENV) and RPL18 in human hepatic cells (Huh-7) exhibits a similar significance [83]. The above researches describe the upregulating role of RPL18 on virus translation.…”

Section: Interaction Between Viral Proteins and Ribosomal Proteinsmentioning

confidence: 90%

Regulation of Ribosomal Proteins on Viral Infection

2019

Cells

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Ribosomal proteins (RPs), in conjunction with rRNA, are major components of ribosomes involved in the cellular process of protein biosynthesis, known as “translation”. The viruses, as the small infectious pathogens with limited genomes, must recruit a variety of host factors to survive and propagate, including RPs. At present, more and more information is available on the functional relationship between RPs and virus infection. This review focuses on advancements in my own understanding of critical roles of RPs in the life cycle of viruses. Various RPs interact with viral mRNA and proteins to participate in viral protein biosynthesis and regulate the replication and infection of virus in host cells. Most interactions are essential for viral translation and replication, which promote viral infection and accumulation, whereas the minority represents the defense signaling of host cells by activating immune pathway against virus. RPs provide a new platform for antiviral therapy development, however, at present, antiviral therapeutics with RPs involving in virus infection as targets is limited, and exploring antiviral strategy based on RPs will be the guides for further study.

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Dengue virus NS1 protein interacts with the ribosomal protein RPL18: This interaction is required for viral translation and replication in Huh-7 cells

Cited by 74 publications

References 55 publications

Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses

Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses

RPLP1 and RPLP2 Are Essential Flavivirus Host Factors That Promote Early Viral Protein Accumulation

Regulation of Ribosomal Proteins on Viral Infection

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