A new inhibitor of apoptosis from vaccinia virus and eukaryotes.

Caroline Gubser,Frank J M Van Kuppeveld,Xin Lu,Daniele Bergamaschi,Geoffrey L Smith,Michael Hollinshead,Beth Levine

doi:10.1371/journal.ppat.0030017

Abstract

A new apoptosis inhibitor is described from vaccinia virus, camelpox virus, and eukaryotic cells. The inhibitor is a hydrophobic, multiple transmembrane protein that is resident in the Golgi and is named GAAP (Golgi anti-apoptotic protein). Stable expression of both viral GAAP (v-GAAP) and human GAAP (h-GAAP), which is expressed in all human tissues tested, inhibited apoptosis induced by intrinsic and extrinsic apoptotic stimuli. Conversely, knockout of h-GAAP by siRNA induced cell death by apoptosis. v-GAAP and h-GAAP display overlapping functions as shown by the ability of v-GAAP to complement for the loss of h-GAAP. Lastly, deletion of the v-GAAP gene from vaccinia virus did not affect virus replication in cell culture, but affected virus virulence in a murine infection model. This study identifies a new regulator of cell death that is highly conserved in evolution from plants to insects, amphibians, mammals, and poxviruses.

Highlights

Cell death is the result of either necrosis or apoptosis
This study describes the identification and characterisation of a new poxvirus anti-apoptotic protein that is located in the Golgi and is called viral Golgi anti-apoptotic protein. v-Golgi antiapoptotic protein (GAAP) is non-essential for virus replication in cell culture but affects virus virulence in a murine model of infection
GAAPs are extremely well conserved with closely related proteins in plants, insects, amphibia, and mammals, the viral and human counterparts sharing a striking 73% sequence identity

Summary

Introduction

Necrosis is the outcome of severe and acute injury, whereas apoptosis is an evolutionarily conserved, strictly regulated, energy-dependent process of cell suicide responsible for the ordered removal of superfluous, aged, or damaged cells, including virus-infected cells [1]. Proteins encoded in the terminal regions of the genome are mostly non-essential for virus replication but affect virus virulence, host range, or the host responses to infection. This group of proteins is numerous and includes those that are secreted from the infected cell and bind complement factors, interferons, cytokines, and chemokines [10]. Poxvirus immunomodulatory proteins may be intracellular and interfere with signalling pathways regulating cellular gene expression or apoptosis. Several poxvirus proteins that inhibit apoptosis have been described (for review, see [11])

Methods

Results

Discussion

Conclusion