Disruption of the ribosomal P complex leads to stress-induced autophagy

Castro, Ana Artero; Pérez-Alea, Mileidys; Feliciano, Andrea; Ja, Leal; Genestar, M; Castellví, Josep; S, Ramón y Cajal; Me, Lleonart

doi:10.1080/15548627.2015.1063764

Cited by 62 publications

(46 citation statements)

References 69 publications

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“…It is not clear why RPLP1/2 knockdown causes different effects on cellular translation in these cell lines. However, these observations are in agreement with previous reports that showed variable effects on cellular translation upon RPLP1/2 depletion (30)(31)(32). Importantly, these data indicate that the potent reductions we observed in flavivirus infectivity upon RPLP1/2 knockdown cannot be explained by a generalized inhibition of cellular translation.…”

Section: Resultssupporting

confidence: 82%

“…RPLP1/2 were also required for DENV-2 infection of A. aegypti mosquitoes, highlighting a conserved role for these host factors across different species. RPLP1/2 were not essential for protein synthesis in human cells, consistent with previous reports (30)(31)(32). Two lines of evidence implicate RPLP1/2 as drivers of flavivirus translation: (i) the early accumulation of DENV-2-expressed luciferase and NS3 was reduced in RPLP1/2 knockdown cells after infection, and (ii) RPLP1/2 depletion reduced expression levels of structural proteins in heterologous cell-based assays that bypass viral entry.…”

Section: Discussionsupporting

confidence: 74%

“…The stalk acts in recruitment of elongation factor eEF2, which functions in GTP-dependent ribosomal translocation (29). However, previous studies have reported little (ϳ20% reduction) to no change in global translation when RPLP1/2 are depleted in cells (30)(31)(32).…”

Section: Abstract Flavivirus Ribosomal Proteins Translationmentioning

confidence: 94%

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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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Section: Resultssupporting

confidence: 82%

Section: Discussionsupporting

confidence: 74%

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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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“…mt-Rnr1 encodes the catalytic subunit of the ribonucleotide reductase complex that is the rate-limiting step in dNTP production – vital for a number of biological processes, including mitochondrial replication and DNA repair. Rplp0 is a member of the ribosomal P complex involved in protein synthesis; down-regulation of this complex leads to autophagy, ER stress, and the unfolded protein response (Artero-Castro et al., 2015). Hspa8 is also involved in chaperone-mediated autophagy (Chiang, Terlecky, Plant, & Dice, 1989; Kaushik & Cuervo, 2012).…”

Section: Discussionmentioning

confidence: 99%

Genetic divergence in the transcriptional engram of chronic alcohol abuse: A laser-capture RNA-seq study of the mouse mesocorticolimbic system

Mulligan

Mozhui

Pandey

et al. 2017

Alcohol

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Genetic factors that influence the transition from initial drinking to dependence remain enigmatic. Recent studies have leveraged chronic intermittent ethanol (CIE) paradigms to measure changes in brain gene expression in a single strain at 0, 8, 72 h, and even 7 days following CIE. We extend these findings using LCM RNA-seq to profile expression in 11 brain regions in two inbred strains – C57BL/6J (B6) and DBA/2J (D2) – 72 h following multiple cycles of ethanol self-administration and CIE. Linear models identified differential expression based on treatment, region, strain, or interactions with treatment. Nearly 40% of genes showed a robust effect (FDR < 0.01) of region, and hippocampus CA1, cortex, bed nucleus stria terminalis, and nucleus accumbens core had the highest number of differentially expressed genes after treatment. Another 8% of differentially expressed genes demonstrated a robust effect of strain. As expected, based on similar studies in B6, treatment had a much smaller impact on expression; only 72 genes (p < 0.01) are modulated by treatment (independent of region or strain). Strikingly, many more genes (415) show a strain-specific and largely opposite response to treatment and are enriched in processes related to RNA metabolism, transcription factor activity, and mitochondrial function. Over 3 times as many changes in gene expression were detected in D2 compared to B6, and weighted gene co-expression network analysis (WGCNA) module comparison identified more modules enriched for treatment effects in D2. Substantial strain differences exist in the temporal pattern of transcriptional neuroadaptation to CIE, and these may drive individual differences in risk of addiction following excessive alcohol consumption.

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“…Последнему способствует снижение экспрес-сии кислого рибосомального белка 60S [13]. Изме-нение процессов трансляции, очевидно, вносит су-щественный вклад в развитие выявленных нами посттрансляционных модификаций белков плацен- Примечание.…”

Section: результаты и обсуждениеunclassified

Post-translational modifications and differential expression of proteins in placental insufficiency

Pogorelova¹,

Gunko²,

Никашина³

et al. 2016

Probl. reprod.

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Disruption of the ribosomal P complex leads to stress-induced autophagy

Cited by 62 publications

References 69 publications

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

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

Genetic divergence in the transcriptional engram of chronic alcohol abuse: A laser-capture RNA-seq study of the mouse mesocorticolimbic system

Post-translational modifications and differential expression of proteins in placental insufficiency

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