Phosphorylation of the Viral Nonstructural Protein NS1 during MVMp Infection of A9 Cells

Bär

Lachmann

et al. 2009

J Virol

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The propagation of autonomous parvoviruses is strongly dependent on the phosphorylation of the major nonstructural protein NS1 by members of the protein kinase C (PKC) family. Minute virus of mice (MVM) replication is accompanied by changes in the overall phosphorylation pattern of NS1, which is newly modified at consensus PKC sites. These changes result, at least in part, from the ability of MVM to modulate the PDK-1/PKC pathway, leading to activation and redistribution of both PDK-1 and PKC . We show that proteins of the ezrin-radixin-moesin (ERM) family are essential for virus propagation and spreading through their functions as adaptors for PKC . MVM infection led to redistribution of radixin and moesin in the cell, resulting in increased colocalization of these proteins with PKC . Radixin was found to control the PKCdriven phosphorylation of NS1 and newly synthesized capsids in vivo. Conversely, radixin phosphorylation and activation were driven by the NS1/CKII␣ complex. Altogether, these data argue for ERM proteins being both targets and modulators of parvovirus infection.

Section: Resultsmentioning

confidence: 84%

mentioning

confidence: 87%

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Ezrin-Radixin-Moesin Family Proteins Are Involved in Parvovirus Replication and Spreading

Bär

Lachmann

et al. 2009

J Virol

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“…PV-induced DDR signaling is mediated by activation of ATM but not ATR; is characterized by phosphorylation of H2AX, NBS1, RPA32, CHK2, and P53; and results in accumulation of DNA repair proteins in viral replication centers (16,17). Consequently, cell-cycle arrest after PV infection is observed at the S-G 2 transition or G 2 phase depending on the virus and cell type (27,28). It is associated with upregulation of cell-cycle control proteins such as CDK1, CCNB1/cyclinB1, CDKN1A/p21/Cip1, CDKN1B/p27/Kip1, and RLB2/p130 (27,29,30).…”

Section: Cell Disturbances and Pv Oncolysismentioning

confidence: 99%

Molecular Pathways: Rodent Parvoviruses—Mechanisms of Oncolysis and Prospects for Clinical Cancer Treatment

Clinical Cancer Research

Lacroix

Marchini

et al. 2012

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Rodent parvoviruses (PV) are recognized for their intrinsic oncotropism and oncolytic activity, which contribute to their natural oncosuppressive effects. Although PV uptake occurs in most host cells, some of the subsequent steps leading to expression and amplification of the viral genome and production of progeny particles are upregulated in malignantly transformed cells. By usurping cellular processes such as DNA replication, DNA damage response, and gene expression, and/or by interfering with cellular signaling cascades involved in cytoskeleton dynamics, vesicular integrity, cell survival, and death, PVs can induce cytostasis and cytotoxicity. Although productive PV infections normally culminate in cytolysis, virus spread to neighboring cells and secondary rounds of infection, even abortive infection or the sole expression of the PV nonstructural protein NS1, is sufficient to cause significant tumor cell death, either directly or indirectly (through activation of host immune responses). This review highlights the molecular pathways involved in tumor cell targeting by PVs and in PV-induced cell death. It concludes with a discussion of the relevance of these pathways to the application of PVs in cancer therapy, linking basic knowledge of PV-host cell interactions to preclinical assessment of PV oncosuppression. Clin Cancer Res; 18(13); 3516-23. Ó2012 AACR.

“…The cytotoxicity of NS1 correlates with its ability to bind casein kinase II␣ (CKII␣), the catalytic subunit of the cellular casein kinase II, and suppression of CKII activity during infection protects cells from PV-induced cytopathic effects (CPE) (5). This correlation suggests that NS1-mediated modulation of cellular protein kinase (PK) activity could influence both the phosphorylation of NS1 itself (6) and multiple facets of cell metabolism, including signaling cascades and cytoskeleton dynamics, recently shown to be perturbed upon PV infection (5,7,8,10; and S. Lachmann, S. Bär, J.R., and J.P.F.N., unpublished work).…”

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confidence: 99%

A viral adaptor protein modulating casein kinase II activity induces cytopathic effects in permissive cells

Proc. Natl. Acad. Sci. U.S.A.

Rommelaere

2007

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Autonomous parvoviruses induce severe morphological and physiological alterations in permissive host cells, eventually leading to cell lysis and release of progeny virions. Viral cytopathic effects (CPE) result from specific rearrangements and destruction of cytoskeletal micro-and intermediate filaments. We recently reported that inhibition of endogenous casein kinase II (CKII) protects target cells from parvovirus minute virus of mice (MVM)-induced CPE, pointing to this kinase as an effector of MVM toxicity. The present work shows that the parvoviral NS1 protein mediates CKII-dependent cytoskeletal alterations and cell death. NS1 can act as an adaptor molecule, linking the cellular protein kinase CKII␣ to tropomyosin and thus modulating the substrate specificity of the kinase. This action results in an altered tropomyosin phosphorylation pattern both in vitro and in living cells. The capacity of NS1 to induce CPE was impaired by mutations abolishing binding with either CKII␣ or tropomyosin. The cytotoxic adaptor function of NS1 was confirmed with fusion peptides, where the tropomyosinbinding domain of NS1 and CKII␣ are physically linked. These adaptor peptides were able to mimic NS1 in its ability to induce death of transformed MVM-permissive cells.parvovirus minute virus of mice ͉ protein-protein interactions ͉ tropomyosin ͉ protein kinase specificity R odent parvoviruses (PVs) are promising candidates for the virotherapy of cancer because they exert oncolytic action without showing pathogenicity (1). The PV minute virus of mice (MVM) consists of a small, icosahedral nonenveloped capsid containing a single-stranded 5.1-kb linear DNA. During productive infection, MVM induces dramatic morphological and physiological changes in transformed mouse fibroblasts, culminating in cell death and lysis. The cytotoxicity of MVM is attributed mainly to the large nonstructural protein NS1. This 83-kDa multifunctional viral product is endowed with enzymatic and nonenzymatic properties, enabling it to control various processes necessary for progeny particle production and spreading (for a review, see ref.2). Independently of its functions directly involved in particle production, NS1 exerts specific activities that jeopardize the integrity and survival of infected cells (3, 4). The ability of NS1 to interact physically with host proteins is assumed to play an important role in its cytotoxicity. The interaction of NS1 with proteins involved in DNA replication and transcription suggests that scavenging mechanisms may contribute to NS1-triggered perturbation of host cells, but recent data indicate that NS1 could act in a more specific manner, e.g., by modulating the activity of some partner proteins. The cytotoxicity of NS1 correlates with its ability to bind casein kinase II␣ (CKII␣), the catalytic subunit of the cellular casein kinase II, and suppression of CKII activity during infection protects cells from PV-induced cytopathic effects (CPE) (5). This correlation suggests that NS1-mediated modulation of cellular protein kinase...