The Coxsackievirus 2B Protein Suppresses Apoptotic Host Cell Responses by Manipulating Intracellular Ca2+ Homeostasis

Michelangelo Campanella, Arjan S. De Jong, Kjerstin W H Lanke, Willem J G Melchers, Peter H G M Willems, Paolo Pinton, Rosario Rizzuto, Frank J M Van Kuppeveld

Research output: Contribution to journalArticle

Abstract

Enteroviruses, small cytolytic RNA viruses, confer an antiapoptotic state to infected cells in order to suppress infection-limiting apoptotic host cell responses. This antiapoptotic state also lends protection against cell death induced by metabolic inhibitors like actinomycin D and cycloheximide. The identity of the viral antiapoptotic protein and the underlying mechanism are unknown. Here, we provide evidence that the coxsackievirus 2B protein modulates apoptosis by manipulating intracellular Ca2+ homeostasis. Using fluorescent Ca2+ indicators and organelle-targeted aequorins, we demonstrate that ectopic expression of 2B in HeLa cells decreases the Ca 2+ content of both the endoplasmic reticulum and the Golgi, resulting in down-regulation of Ca2+ signaling between these stores and the mitochondria, and increases the influx of extracellular Ca 2+. In our studies of the physiological importance of the 2B-induced alterations in Ca2+ signaling, we found that the expression of 2B suppressed caspase activation and apoptotic cell death induced by various stimuli, including actinomycin D and cycloheximide. Mutants of 2B that were defective in reducing the Ca2+ content of the stores failed to suppress apoptosis. These data implicate a functional role of the perturbation of intracellular Ca2+ compartmentalization in the enteroviral strategy to suppress intrinsic apoptotic host cell responses. The putative down-regulation of an endoplasmic reticulum-dependent apoptotic pathway is discussed.

Original languageEnglish
Pages (from-to)18440-18450
Number of pages11
JournalJournal of Biological Chemistry
Volume279
Issue number18
DOIs
Publication statusPublished - Apr 30 2004

ASJC Scopus subject areas

  • Biochemistry

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    Campanella, M., De Jong, A. S., Lanke, K. W. H., Melchers, W. J. G., Willems, P. H. G. M., Pinton, P., Rizzuto, R., & Van Kuppeveld, F. J. M. (2004). The Coxsackievirus 2B Protein Suppresses Apoptotic Host Cell Responses by Manipulating Intracellular Ca2+ Homeostasis. Journal of Biological Chemistry, 279(18), 18440-18450. https://doi.org/10.1074/jbc.M309494200