Autophagic Clearance of Sin Nombre Hantavirus Glycoprotein Gn Promotes Virus Replication in Cells

Hussein, Islam T. M.; Cheng, Erdong; Ganaie, Safder S.; Werle, M. J.; Sheema, Sheema; Haque, Absarul; Mir, Mohammad A.

doi:10.1128/jvi.07204-11

Cited by 30 publications

(48 citation statements)

References 46 publications

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“…When values were normalized to actin levels, the levels of the viral glycoproteins Gn and Gc were reduced 72% and 53%, respectively, and appeared more sensitive to 0.1 M temsirolimus than the viral nucleocapsid levels (reduced 32%). We hypothesize that the rapid Gn turnover observed by Hussein et al contributes to increased Gn sensitivity (47). The inhibitory effects on viral protein expression were observed at a concentration 100-fold below the concentration for 50% cellular toxicity (CC 50 ) (10.9 Ϯ 1.9 M) measured over the same time period (see Fig.…”

Section: Resultsmentioning

confidence: 78%

“…Previous work from our laboratory found that SNV Gn colocalized with LAMP1 within infected cells, and we hypothesized that the Gn-specific antibody recognized misfolded or degraded Gn within lysosomes (46). Also, Hussein et al recently demonstrated that overexpressed Gn colocalized with the autophagosomal marker LC3, and they hypothesized that autophagic turnover of Gn was necessary for viral replication (47). Therefore, Gn turnover or direct Gn activity at lysosomes might maintain mTORC1 in an active state during viral replication.…”

Section: Discussionmentioning

confidence: 99%

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Host mTORC1 Signaling Regulates Andes Virus Replication

McNulty

Flint

Nichol

et al. 2013

J Virol

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Hantavirus pulmonary syndrome (HPS) is a severe respiratory disease characterized by pulmonary edema, with fatality rates of 35 to 45%. Disease occurs following infection with pathogenic New World hantaviruses, such as Andes virus (ANDV), which targets lung microvascular endothelial cells. During replication, the virus scavenges 5=-m 7 G caps from cellular mRNA to ensure efficient translation of viral proteins by the host cell cap-dependent translation machinery. In cells, the mammalian target of rapamycin (mTOR) regulates the activity of host cap-dependent translation by integrating amino acid, energy, and oxygen availability signals. Since there is no approved pharmacological treatment for HPS, we investigated whether inhibitors of the mTOR pathway could reduce hantavirus infection. Here, we demonstrate that treatment with the FDA-approved rapamycin analogue temsirolimus (CCI-779) blocks ANDV protein expression and virion release but not entry into primary human microvascular endothelial cells. This effect was specific to viral proteins, as temsirolimus treatment did not block host protein synthesis. We confirmed that temsirolimus targeted host mTOR complex 1 (mTORC1) and not a viral protein, as knockdown of mTORC1 and mTORC1 activators but not mTOR complex 2 components reduced ANDV replication. Additionally, primary fibroblasts from a patient with tuberous sclerosis exhibited increased mTORC1 activity and increased ANDV protein expression, which were blocked following temsirolimus treatment. Finally, we show that ANDV glycoprotein Gn colocalized with mTOR and lysosomes in infected cells. Together, these data demonstrate that mTORC1 signaling regulates ANDV replication and suggest that the hantavirus Gn protein may modulate mTOR and lysosomal signaling during infection, thus bypassing the cellular regulation of translation.

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Section: Resultsmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Host mTORC1 Signaling Regulates Andes Virus Replication

McNulty

Flint

Nichol

et al. 2013

J Virol

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“…Their active replication implies that viral mRNAs actively compete with host cell transcripts for the same translation machinery. We recently showed that hantaviruses may use N-mediated translation strategy to facilitate the translation of viral transcripts in the host cell [26]. We demonstrated that a monomeric N molecule binds to the mRNA 5′ cap and a trimeric N molecule binds to the heptanucleotide sequence GUAGUAG of the viral mRNA 5′ UTR [26].…”

Section: Resultsmentioning

confidence: 99%

“…We recently showed that hantaviruses may use N-mediated translation strategy to facilitate the translation of viral transcripts in the host cell [26]. We demonstrated that a monomeric N molecule binds to the mRNA 5′ cap and a trimeric N molecule binds to the heptanucleotide sequence GUAGUAG of the viral mRNA 5′ UTR [26]. We proposed that monomeric and trimeric N molecules individually associated with the 5′ cap and the heptanucleotide sequence undergo intra-molecular interaction and generate a tetrameric ribosome loading pad at which N-associated ribosomes are efficiently loaded by an unknown mechanism, leading to the efficient translation of viral mRNAs in comparison to the cellular transcripts that lack the viral heptanucleotide sequence in their 5′UTR [22].…”

Section: Resultsmentioning

confidence: 99%

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Ribosomal protein S19-binding domain provides insights into hantavirus nucleocapsid protein-mediated translation initiation mechanism

Ganaie

Haque

Cheng

et al. 2014

Biochemical Journal

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The hantaviral zoonotic diseases pose significant threat to human health due to the lack of potential antiviral therapeutics or a vaccine against hantaviruses. Sin Nombre hantavirus nucleocapsid protein (N) augments mRNA translation. N binds to both the mRNA 5′ cap and 40S ribosomal subunit via ribosomal protein S19 (RPS19). N with the assistance of viral mRNA 5′ untranslated region (UTR) preferentially favors the translation of downstream open reading frame. We identified and characterized the RPS19 binding domain at the N-terminus of N. Its deletion did not influence the secondary structure but impacted the conformation of trimeric N molecules. N variant lacking the RPS19 binding region was able to bind both the mRNA 5′ cap and panhandle like structure, formed by the termini of viral genomic RNA. In addition, N variant formed stable trimers similar to wild type N. Use of this variant in multiple experiments provided insights into the mechanism of ribosome loading during N-mediated translation strategy. Our studies suggest that N molecules individually associated with mRNA 5′ cap and RPS19 of the 40S ribosomal subunit undergo N-N interaction to facilitate the engagement of N associated ribosomes at the mRNA 5′ cap. These studies have revealed new targets for therapeutic intervention of hantavirus infection.

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The nucleocapsid protein of hantaviruses: much more than a genome-wrapping protein

Reuter

Krüger

2017

Virus Genes

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The nucleocapsid (N) protein of hantaviruses represents an impressive example of a viral multifunctional protein. It encompasses properties as diverse as genome packaging, RNA chaperoning, intracellular protein transport, DNA degradation, intervention in host translation, and restricting host immune responses. These functions all rely on the capability of N to interact with RNA and other viral and cellular proteins. We have compiled data on the N protein of different hantavirus species together with information of the recently published three-dimensional structural data of the protein. The array of diverse functional activities accommodated in the hantaviral N protein goes far beyond to be a static structural protein and makes it an interesting target in the development of antiviral therapeutics.

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Autophagic Clearance of Sin Nombre Hantavirus Glycoprotein Gn Promotes Virus Replication in Cells

Cited by 30 publications

References 46 publications

Host mTORC1 Signaling Regulates Andes Virus Replication

Host mTORC1 Signaling Regulates Andes Virus Replication

Ribosomal protein S19-binding domain provides insights into hantavirus nucleocapsid protein-mediated translation initiation mechanism

The nucleocapsid protein of hantaviruses: much more than a genome-wrapping protein

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