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Molecular & Cellular Proteomics 8:805-815, 2009.
© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Identification of Replication-competent HSV-1 Cgal⁺ Strain Signaling Targets in Human Hepatoma Cells by Functional Organelle Proteomics^*,S

Enrique Santamaría, María I. Mora, Corinne Potel, Joaquín Fernández-Irigoyen, Elvira Carro-Roldán, Rubén Hernández-Alcoceba, Jesús Prieto, Alberto L. Epstein and Fernando J. Corrales^,¶

From the Division of Hepatology and Gene Therapy, Proteomics Unit, Centre for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain and Université Lyon 1, Lyon F-69003, France, CNRS, UMR5534, Centre de Génétique Moleculaire et Cellulaire, 16 rue Dubois, Villeurbanne, F-69622, France

In the present work, we have attempted a comprehensive analysis of cytosolic and microsomal proteomes to elucidate the signaling pathways impaired in human hepatoma (Huh7) cells upon herpes simplex virus type 1 (HSV-1; Cgal⁺) infection. Using a combination of differential in-gel electrophoresis and nano liquid chromatography/tandem mass spectrometry, 18 spots corresponding to 16 unique deregulated cellular proteins were unambiguously identified, which were involved in the regulation of essential processes such as apoptosis, mRNA processing, cellular structure and integrity, signal transduction, and endoplasmic-reticulum-associated degradation pathway. Based on our proteomic data and additional functional studies target proteins were identified indicating a late activation of apoptotic pathways in Huh7 cells upon HSV-1 Cgal⁺ infection. Additionally to changes on RuvB-like 2 and Bif-1, down-regulation of Erlin-2 suggests stimulation of Ca²⁺-dependent apoptosis. Moreover, activation of the mitochondrial apoptotic pathway results from a time-dependent multi-factorial impairment as inferred from the stepwise characterization of constitutive pro- and anti-apoptotic factors. Activation of serine-threonine protein phosphatase 2A (PP2A) was also found in Huh7 cells upon HSV-1 Cgal⁺ infection. In addition, PP2A activation paralleled dephosphorylation and inactivation of downstream mitogen-activated protein (MAP) kinase pathway (MEK, ERK) critical to cell survival and activation of proapoptotic Bad by dephosphorylation of Ser-112. Taken together, our results provide novel molecular information that contributes to define in detail the apoptotic mechanisms triggered by HSV-1 Cgal⁺ in the host cell and lead to the implication of PP2A in the transduction of cell death signals and cell survival pathway arrest.

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