Reciprocal Regulation of AKT and MAP Kinase Dictates Virus-Host Cell Fusion

Sharma, Nisha; Mani, Prashant; Nandwani, Neha; Mishra, Rajakishore; Rana, Ajay; Sarkar, Debi P.

doi:10.1128/jvi.01940-09

Cited by 14 publications

(24 citation statements)

References 61 publications

(78 reference statements)

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“…2B). These analyses showed significant overrepresentation of phosphoproteins involved in MAPK pathways, ERK/MAPK, p38, and JNK signaling, which all are known to be activated during SeV infection . Our data also indicates that Rho family of GTPases and HIPPO signaling was activated during infection.…”

Section: Resultssupporting

confidence: 65%

Phosphoproteome characterization reveals that Sendai virus infection activates mTOR signaling in human epithelial cells

et al. 2015

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Sendai virus (SeV) is a common respiratory pathogen in mice, rats, and hamsters. Host cell recognition of SeV is mediated by pathogen recognition receptors, which recognize viral components and induce intracellular signal transduction pathways that activate the antiviral innate immune response. Viruses use host proteins to control the activities of signaling proteins and their downstream targets, and one of the most important host protein modifications regulated by viral infection is phosphorylation. In this study, we used phosphoproteomics combined with bioinformatics to get a global view of the signaling pathways activated during SeV infection in human lung epithelial cells. We identified altogether 1347 phosphoproteins, and our data shows that SeV infection induces major changes in protein phosphorylation affecting the phosphorylation of almost one thousand host proteins. Bioinformatics analysis showed that SeV infection activates known pathways including MAPK signaling, as well as signaling pathways previously not linked to SeV infection including Rho family of GTPases, HIPPO signaling, and mammalian target of rapamycin (mTOR)-signaling pathway. Further, we performed functional studies with mTOR inhibitors and siRNA approach, which revealed that mTOR signaling is needed for both the host IFN response as well as viral protein synthesis in SeV-infected human lung epithelial cells.

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Section: Resultssupporting

confidence: 65%

Phosphoproteome characterization reveals that Sendai virus infection activates mTOR signaling in human epithelial cells

et al. 2015

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“…Additionally, it was demonstrated that activation of ERK1/2 is required for viral entry using Sendai virus-like particles as a model for Paramyxovirus infection [48]. In this study, ERK1 was identified in RSV infected cells only, and ERK2 was detected with higher abundance in infected cells.…”

Section: Discussionmentioning

confidence: 61%

Label-free quantitative proteomics reveals regulation of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) and 5'-3'-exoribonuclease 2 (XRN2) during respiratory syncytial virus infection

Ternette

Wright

Kramer

et al. 2011

Virol J

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A large quantitative study was carried out to compare the proteome of respiratory syncytial virus (RSV) infected versus uninfected cells in order to determine novel pathways regulated during viral infection. RSV infected and mock-infected HEp2 cells were lysed and proteins separated by preparative isoelectric focussing using offgel fractionation. Following tryptic digestion, purified peptides were characterized using label-free quantitative expression profiling by nano-ultra performance liquid chromatography coupled to electrospray ionisation mass spectrometry with collision energy ramping for all-ion fragmentation (UPLC-MSE). A total of 1352 unique cellular proteins were identified and their abundance compared between infected and non-infected cells. Ingenuity pathway analysis revealed regulation of several central cellular metabolic and signalling pathways during infection. Selected proteins that were found regulated in RSV infected cells were screened by quantitative real-time PCR for their regulation on the transcriptional level. Synthesis of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) and 5'-3'-exoribonuclease 2 (XRN2) mRNAs were found to be highly induced upon RSV infection in a time dependent manner. Accordingly, IFIT3 protein levels accumulated during the time course of infection. In contrast, little variation was observed in XRN2 protein levels, but different forms were present in infected versus non-infected cells. This suggests a role of these proteins in viral infection, and analysis of their function will shed further light on mechanisms of RNA virus replication and the host cell defence machinery.

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“…Subsequently, DC-SIGN engagement can initiate both MAPK and phosphatidylinositol 3-kinase (PI3K)/ mTOR signaling with phosphorylation of ERK1/2 and Akt (5,7,38,48). ERK1/2 signaling is involved in infection, replication, and host responses to a number of pathogens (19), particularly viruses (41,48,49,61). PI3K and mTOR have well-defined roles in controlling activation of adaptive immune responses but have now also been shown to be critical in regulation of innate immunity (58).…”

Section: Discussionmentioning

confidence: 99%

“…Ligand binding to or antibody crosslinking of DC/L-SIGN has been shown to result in phosphorylation of multiple cellular kinase pathways, including ERK1/2, p38/ mitogen-activated protein kinase (MAPK), Akt, and c-Raf (5,7,38,48). Similarly, RSV phosphorylates ERK1/2 during infection of epithelial cells (49). As moderate changes were observed in DC maturation and cytokine and chemokine production following DC/L-SIGN neutralization and RSV exposure, we examined the impact of RSV G on signaling events in 3T3 parent cells and 3T3-DC-SIGN and 3T3-L-SIGN transfectants.…”

Section: Neutralization Of Dc/l-sign Does Not Reduce Rsv Infection Ofmentioning

confidence: 99%

Respiratory Syncytial Virus Glycoprotein G Interacts with DC-SIGN and L-SIGN To Activate ERK1 and ERK2

Johnson

McLellan

Graham

2012

J Virol

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Respiratory syncytial virus (RSV) interaction with epithelial and dendritic cells (DCs) is known to require divalent cations, suggesting involvement of C-type lectins. RSV infection and maturation of primary human DCs are reduced in a dose-dependent manner by EDTA. Therefore, we asked whether RSV infection involves DC-SIGN (CD209) or its isoform L-SIGN (CD299) (DC-SIGN/R). Using surface plasmon resonance analysis, we demonstrated that the attachment G glycoprotein of RSV binds both DC- and L-SIGN. However, neutralization of DC- and L-SIGN on primary human DCs did not inhibit RSV infection, demonstrating that interactions between RSV G and DC- or L-SIGN are not required for productive infection. Thus, neither DC- nor L-SIGN represents a functional receptor for RSV. However, inhibition of these interactions increased DC activation, as evidenced by significantly higher levels of alpha interferon (IFN-α), MIP-1α, and MIP-1β in plasmacytoid DCs (pDCs) exposed to RSV after neutralization of DC-and L-SIGN. To understand the molecular interactions involved, intracellular signaling events triggered by purified RSV G glycoprotein were examined in DC- and L-SIGN-transfected 3T3 cells. RSV G interaction with DC- or L-SIGN was shown to stimulate ERK1 and ERK2 phosphorylation, with statistically significant increases relative to mock-infected cells. Neutralization of DC- and L-SIGN reduced ERK1/2 phosphorylation. With increased DC activation following DC- and L-SIGN neutralization and RSV exposure, these data demonstrate that the signaling events mediated by RSV G interactions with DC/L-SIGN are immunomodulatory and diminish DC activation, which may limit induction of RSV-specific immunity.

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Reciprocal Regulation of AKT and MAP Kinase Dictates Virus-Host Cell Fusion

Abstract: Viruses of the

Cited by 14 publications

References 61 publications

Phosphoproteome characterization reveals that Sendai virus infection activates mTOR signaling in human epithelial cells

Phosphoproteome characterization reveals that Sendai virus infection activates mTOR signaling in human epithelial cells

Label-free quantitative proteomics reveals regulation of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) and 5'-3'-exoribonuclease 2 (XRN2) during respiratory syncytial virus infection

Respiratory Syncytial Virus Glycoprotein G Interacts with DC-SIGN and L-SIGN To Activate ERK1 and ERK2

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