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Avian Reovirus Protein p17 Functions as a Nucleoporin Tpr Suppressor Leading to Activation of p53, p21 and PTEN and Inactivation of PI3K/AKT/mTOR and ERK Signaling Pathways.

Huang WR, Chiu HC, Liao TL, Chuang KP, Shih WL, Liu HJ - PLoS ONE (2015)

Bottom Line: To activate PTEN, p17 is able to promote β-arrestin-mediated PTEN translocation from the cytoplasm to the plasma membrane via a Rock-1-dependent manner.The accumulation of p53 in the nucleus induces the PTEN- and p21-mediated downregulation of cyclin D1 and CDK4.Furthermore, Tpr and CDK4 knockdown increased virus production in contrast to depletion of p53, PTEN, and LC3 reducing virus yield.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology, National Chung Hsing University, Taichung, 402, Taiwan.

ABSTRACT
Avian reovirus (ARV) protein p17 has been shown to regulate cell cycle and autophagy by activation of p53/PTEN pathway; nevertheless, it is still unclear how p53 and PTEN are activated by p17. Here, we report for the first time that p17 functions as a nucleoporin Tpr suppressor that leads to p53 nuclear accumulation and consequently activates p53, p21, and PTEN. The nuclear localization signal (119IAAKRGRQLD128) of p17 has been identified for Tpr binding. This study has shown that Tpr suppression occurs by p17 interacting with Tpr and by reducing the transcription level of Tpr, which together inhibit Tpr function. In addition to upregulation of PTEN by activation of p53 pathway, this study also suggests that ARV protein p17 acts as a positive regulator of PTEN. ARV p17 stabilizes PTEN by stimulating phosphorylation of cytoplasmic PTEN and by elevating Rak-PTEN association to prevent it from E3 ligase NEDD4-1 targeting. To activate PTEN, p17 is able to promote β-arrestin-mediated PTEN translocation from the cytoplasm to the plasma membrane via a Rock-1-dependent manner. The accumulation of p53 in the nucleus induces the PTEN- and p21-mediated downregulation of cyclin D1 and CDK4. Furthermore, Tpr and CDK4 knockdown increased virus production in contrast to depletion of p53, PTEN, and LC3 reducing virus yield. Taken together, our data suggest that p17-mediated Tpr suppression positively regulates p53, PTEN, and p21 and negatively regulates PI3K/AKT/mTOR and ERK signaling pathways, both of which are beneficial for virus replication.

No MeSH data available.


Related in: MedlinePlus

A model depicting the mechanisms of p17 modulating Tpr, p53, AKT, p21, PTEN, mTORC1 that govern cell cycle and autophagosome formation.This study establishes a new regulatory network of p17 linking Tpr, p53, p21, PTEN, mTORC1, and Rb. p17 suppresses Tpr leading to p53 and p21 nuclear accumulation, which in turn activates p53, p21, and PTEN. Furthermore, it also serves as a positive regulator of PTEN. Activation of PTEN leads to inhibition of ERK and AKT that result in mTORC1 inhibition as well as cyclin D1 and CDK 4 inhibition, leading to Rb activation. This study provides evidences demonstrating that p17 regulates cell cycle through Tpr/p53/PTEN/AKT and Tpr/p53/p21 signaling pathways. By suppressing Tpr, p17 is able to negatively regulate PI3K/AKT/mTORC1 and consequently induce cellular translation shutoff and autophagosome formation enhancing virus replication. →: activation;⊥: Inhibition.
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pone.0133699.g011: A model depicting the mechanisms of p17 modulating Tpr, p53, AKT, p21, PTEN, mTORC1 that govern cell cycle and autophagosome formation.This study establishes a new regulatory network of p17 linking Tpr, p53, p21, PTEN, mTORC1, and Rb. p17 suppresses Tpr leading to p53 and p21 nuclear accumulation, which in turn activates p53, p21, and PTEN. Furthermore, it also serves as a positive regulator of PTEN. Activation of PTEN leads to inhibition of ERK and AKT that result in mTORC1 inhibition as well as cyclin D1 and CDK 4 inhibition, leading to Rb activation. This study provides evidences demonstrating that p17 regulates cell cycle through Tpr/p53/PTEN/AKT and Tpr/p53/p21 signaling pathways. By suppressing Tpr, p17 is able to negatively regulate PI3K/AKT/mTORC1 and consequently induce cellular translation shutoff and autophagosome formation enhancing virus replication. →: activation;⊥: Inhibition.

Mentions: Understanding the molecular basis for ARV interaction with host factors and for ARV-induced changes can shed light on normal cellular events and on the specific ways that ARV gains control over its hosts. A model in Fig 11 illustrates a novel regulatory network of p17. p17 negatively regulates Tpr leading to activation of p53, p21, PTEN, and Rb that are the major regulators of AKT, mTORC1, ERK, CDK4, and E2F-1. It is worth to noting that ARV has evolved mechanisms that alter the physiology of its host cells during infection to increase its replication and to block the host response to its infection in ways that are crucial for completing its life cycle.


Avian Reovirus Protein p17 Functions as a Nucleoporin Tpr Suppressor Leading to Activation of p53, p21 and PTEN and Inactivation of PI3K/AKT/mTOR and ERK Signaling Pathways.

Huang WR, Chiu HC, Liao TL, Chuang KP, Shih WL, Liu HJ - PLoS ONE (2015)

A model depicting the mechanisms of p17 modulating Tpr, p53, AKT, p21, PTEN, mTORC1 that govern cell cycle and autophagosome formation.This study establishes a new regulatory network of p17 linking Tpr, p53, p21, PTEN, mTORC1, and Rb. p17 suppresses Tpr leading to p53 and p21 nuclear accumulation, which in turn activates p53, p21, and PTEN. Furthermore, it also serves as a positive regulator of PTEN. Activation of PTEN leads to inhibition of ERK and AKT that result in mTORC1 inhibition as well as cyclin D1 and CDK 4 inhibition, leading to Rb activation. This study provides evidences demonstrating that p17 regulates cell cycle through Tpr/p53/PTEN/AKT and Tpr/p53/p21 signaling pathways. By suppressing Tpr, p17 is able to negatively regulate PI3K/AKT/mTORC1 and consequently induce cellular translation shutoff and autophagosome formation enhancing virus replication. →: activation;⊥: Inhibition.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526660&req=5

pone.0133699.g011: A model depicting the mechanisms of p17 modulating Tpr, p53, AKT, p21, PTEN, mTORC1 that govern cell cycle and autophagosome formation.This study establishes a new regulatory network of p17 linking Tpr, p53, p21, PTEN, mTORC1, and Rb. p17 suppresses Tpr leading to p53 and p21 nuclear accumulation, which in turn activates p53, p21, and PTEN. Furthermore, it also serves as a positive regulator of PTEN. Activation of PTEN leads to inhibition of ERK and AKT that result in mTORC1 inhibition as well as cyclin D1 and CDK 4 inhibition, leading to Rb activation. This study provides evidences demonstrating that p17 regulates cell cycle through Tpr/p53/PTEN/AKT and Tpr/p53/p21 signaling pathways. By suppressing Tpr, p17 is able to negatively regulate PI3K/AKT/mTORC1 and consequently induce cellular translation shutoff and autophagosome formation enhancing virus replication. →: activation;⊥: Inhibition.
Mentions: Understanding the molecular basis for ARV interaction with host factors and for ARV-induced changes can shed light on normal cellular events and on the specific ways that ARV gains control over its hosts. A model in Fig 11 illustrates a novel regulatory network of p17. p17 negatively regulates Tpr leading to activation of p53, p21, PTEN, and Rb that are the major regulators of AKT, mTORC1, ERK, CDK4, and E2F-1. It is worth to noting that ARV has evolved mechanisms that alter the physiology of its host cells during infection to increase its replication and to block the host response to its infection in ways that are crucial for completing its life cycle.

Bottom Line: To activate PTEN, p17 is able to promote β-arrestin-mediated PTEN translocation from the cytoplasm to the plasma membrane via a Rock-1-dependent manner.The accumulation of p53 in the nucleus induces the PTEN- and p21-mediated downregulation of cyclin D1 and CDK4.Furthermore, Tpr and CDK4 knockdown increased virus production in contrast to depletion of p53, PTEN, and LC3 reducing virus yield.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology, National Chung Hsing University, Taichung, 402, Taiwan.

ABSTRACT
Avian reovirus (ARV) protein p17 has been shown to regulate cell cycle and autophagy by activation of p53/PTEN pathway; nevertheless, it is still unclear how p53 and PTEN are activated by p17. Here, we report for the first time that p17 functions as a nucleoporin Tpr suppressor that leads to p53 nuclear accumulation and consequently activates p53, p21, and PTEN. The nuclear localization signal (119IAAKRGRQLD128) of p17 has been identified for Tpr binding. This study has shown that Tpr suppression occurs by p17 interacting with Tpr and by reducing the transcription level of Tpr, which together inhibit Tpr function. In addition to upregulation of PTEN by activation of p53 pathway, this study also suggests that ARV protein p17 acts as a positive regulator of PTEN. ARV p17 stabilizes PTEN by stimulating phosphorylation of cytoplasmic PTEN and by elevating Rak-PTEN association to prevent it from E3 ligase NEDD4-1 targeting. To activate PTEN, p17 is able to promote β-arrestin-mediated PTEN translocation from the cytoplasm to the plasma membrane via a Rock-1-dependent manner. The accumulation of p53 in the nucleus induces the PTEN- and p21-mediated downregulation of cyclin D1 and CDK4. Furthermore, Tpr and CDK4 knockdown increased virus production in contrast to depletion of p53, PTEN, and LC3 reducing virus yield. Taken together, our data suggest that p17-mediated Tpr suppression positively regulates p53, PTEN, and p21 and negatively regulates PI3K/AKT/mTOR and ERK signaling pathways, both of which are beneficial for virus replication.

No MeSH data available.


Related in: MedlinePlus