Role of AKT Kinase in Measles Virus Replication

Carsillo, Mary; Kim, Dhohyung; Niewiesk, Stefan

doi:10.1128/jvi.01316-09

Cited by 21 publications

(15 citation statements)

References 18 publications

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“…In contrast to examples of viral exploitation of the Akt pathway (3,8,13), a decrease in polymerase activity could indicate that Akt phosphorylation of the NoV RdRp is an antiviral strategy protecting the infected cell. However, this idea may be hard to reconcile with our observation that the Akt phosphorylation event occurs in the most epidemiologically fit genotype (GII.4) and is generally absent from others.…”

mentioning

confidence: 96%

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Norovirus RNA-Dependent RNA Polymerase Is Phosphorylated by an Important Survival Kinase, Akt

Eden

Sharpe

White

et al. 2011

J Virol

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Viruses commonly use host cell survival mechanisms to their own advantage. We show that Akt, an important signaling kinase involved in cell survival, phosphorylates the RNA-dependent RNA polymerase (RdRp) from norovirus, the major cause of gastroenteritis outbreaks worldwide. The Akt phosphorylation of RdRp appears to be a feature unique to the more prevalent norovirus genotypes such as GII.4 and GII.b. This phosphorylation event occurs at a residue (Thr33) located at the interface where the RdRp finger and thumb domains interact and decreases de novo activity of the polymerase. This finding provides fresh insights into virus-host cell interactions.

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mentioning

confidence: 96%

“…Alternatively, not all viruses activate the PI3K/Akt pathway. For example, with measles virus, infection leads to a downregulation of Akt that appears to play a role in immune suppression (8).…”

mentioning

confidence: 99%

Norovirus RNA-Dependent RNA Polymerase Is Phosphorylated by an Important Survival Kinase, Akt

Eden

Sharpe

White

et al. 2011

J Virol

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“…The phosphorylation of both viral and cellular proteins have been shown to play a major role in the life cycle of numerous viruses, many of which exploit critical cellular signaling pathways through the selective activation of cellular phosphatases and kinases 16,31,31,42 . Targeting key regulators of these signaling pathways, such as PP1, holds broad application potential as PP1 regulates an enormous number of cellular functions and is highly conserved among eukaryotic cells.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have shown that PP1 plays a prominent role in viral replication affecting the antiviral response, signal transduction, cell cycle checkpoint control, RNA splicing, and protein synthesis 11–15 . While the significance of cellular kinases for RVFV has been partially described 16–19 , relatively little is known about the impact of cellular phosphatases on viral replication.…”

Section: Introductionmentioning

confidence: 99%

Protein Phosphatase-1 regulates Rift Valley fever virus replication

et al. 2016

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Rift Valley fever virus (RVFV), genus Phlebovirus family Bunyaviridae, is an arthropod-borne virus endemic throughout sub-Saharan Africa. Recent outbreaks have resulted in cyclic epidemics with an increasing geographic footprint, devastating both livestock and human populations. Despite being recognized as an emerging threat, relatively little is known about the virulence mechanisms and host interactions of RVFV. To date there are no FDA approved therapeutics or vaccines for RVF and there is an urgent need for their development. The Ser/Thr protein phosphatase 1 (PP1) has previously been shown to play a significant role in the replication of several viruses. Here we demonstrate for the first time that PP1 plays a prominent role in RVFV replication early on during the viral life cycle. Both siRNA knockdown of PP1α and a novel PP1-targeting small molecule compound 1E7-03, resulted in decreased viral titers across several cell lines. Deregulation of PP1 was found to inhibit viral RNA production, potentially through the disruption of viral RNA transcript/protein interactions, and indicates a potential link between PP1α and the viral L polymerase and nucleoprotein. These results indicate that PP1 activity is important for RVFV replication early on during the viral life cycle and may prove an attractive therapeutic target.

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“…As yet, MV is the only pathogen known to interfere with the activation of this pathway in a contact-dependent manner. This pathway is, however, often activated by viruses because it supports their replication directly or by promoting host cell survival and cell cycle entry [99][100][101][102], yet Akt kinase activation apparently has no impact on replication of an attenuated MV strain in Jurkat T cells [103].…”

Section: Signaling Pathways Targeted By MVmentioning

confidence: 99%

Measles virus-induced immunosuppression: from effectors to mechanisms

Avota

Gassert

Schneider‐Schaulies

2010

Med Microbiol Immunol

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Immunosuppression is the major cause of infant death associated with acute measles. Hallmarks of this generalized modulation of immune functions include: (1) lymphopenia, (2) a prolonged cytokine imbalance consistent with suppression of cellular immunity to secondary infections and (3) silencing of peripheral blood lymphocytes that fail to expand in response to ex vivo stimulation. Lymphopenia results from depletion of T cells by mechanisms also involving MV infection, and expression of the major MV receptor CD150 plays an important role for targeting these cells. Virus transfer to T cells is thought to be mediated by dendritic cells (DCs), which are considered as central to the induction of T-cell silencing and functional skewing. MV interaction modulates functional differentiation of DCs, and thereby expression pattern of costimulatory molecules and soluble mediators. Moreover, MV proteins expressed by these cells actively silence T cells by interfering with signaling pathways essential for T-cell activation. As an essential component of this interference, the MV glycoprotein complex activates cellular sphingomyelinases in a contact-dependent manner, and these are effective at preventing stimulated rearrangements of the actin cytoskeleton and thereby morphological and functional polarization and motility of T cells.

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Role of AKT Kinase in Measles Virus Replication

Cited by 21 publications

References 18 publications

Norovirus RNA-Dependent RNA Polymerase Is Phosphorylated by an Important Survival Kinase, Akt

Norovirus RNA-Dependent RNA Polymerase Is Phosphorylated by an Important Survival Kinase, Akt

Protein Phosphatase-1 regulates Rift Valley fever virus replication

Measles virus-induced immunosuppression: from effectors to mechanisms

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