Viroporins from RNA viruses induce caspase-dependent apoptosis

Abstract

SummaryThe virus-encoded viroporins are known to modify membrane permeability and play an essential role in virus budding. Here, a comparative analysis of the membrane permeabilization capacity of a number of viroporins was performed in baby hamster kidney cells. Synthesis of 6K protein from Sindbis virus, E from mouse hepatitis virus, M2 from influenza A virus, and 2B and 3A from poliovirus enhanced membrane permeability to different extents. We show that two proteins from hepatitis C virus, p7 and NS4A, also display viroporin activity to a level comparable to 6K protein. In addition to their capacity to disrupt ionic cellular homeostasis and promote bacterial cell lysis, the expressed viroporins were able to induce cell death. Degradation of internucleosomal DNA and generation of apoptotic bodies were observed upon viroporin expression. Consistently, cleavage of translation initiation factor 4GI and poly-(ADP-ribose) polymerase indicated activation of effector caspase-3. We found that poliovirus 2B localizes partially in mitochondria and induces an anomalous perinuclear distribution of these organelles. Mitochondria morphology was also altered after expression of other viroporins. Finally, detection of cytochrome c release from mitochondria suggests involvement of the mitochondrial pathway in viroporin-induced apoptosis. These findings suggest that viroporins induce caspase-dependent programmed cell death.

Structural and Functional Aspects of the Small Hydrophobic (SH) Protein in the Human Respiratory Syncytial Virus

“…However, ion channels may also control apoptosis in cells (Szabo et al, 2004;Lang et al, 2005;Burg et al, 2006;Madan et al, 2008). Disruption of cells homeostasis is a common sign of apoptosis, leading to plasma membrane depolarization associated with intracellular cation overload and cell volume decreases due to anion and water efflux (Burg et al, 2006).…”

“…Disruption of cells homeostasis is a common sign of apoptosis, leading to plasma membrane depolarization associated with intracellular cation overload and cell volume decreases due to anion and water efflux (Burg et al, 2006). In fact, the viroporin of Sindbis virus 6K, murine hepatitisvirus E protein, Influenza A M2 protein, HCV p7 protein, poliovirus 2b and 3A protein have been reported to manipulate apoptosis of infected cells (Neznanov et al, 2001;Campanella et al, 2004;Madan et al, 2008). While promotion of apoptosis helps to release the virus, inhibition of apoptosis in host cells during infection gives an advantage to the virus to replicate.…”

Mitochondria as a Favourite Organelle for Invading Viruses

“…Most prominent of these are discussed below: to caspase dependent apoptosis of motor neurons [75]. The polio virus encoded viroprotein 2B induces a perinuclear redistribution of mitochondria and ultimately alters their morphology resulting in MMP (Δψm) loss [76] in a similar fashion as by HBx protein of hepatitis B virus.…”

DIDS blocks a chloride-dependent current that is mediated by the 2B protein of enterovirus 71

“…The 2B expression would perturb ion homeostasis and may disrupt cellular function [8]. Some studies have suggested that 2B induces cell apoptosis via a caspasedependent pathway [14], which may explain the role of 2B in cell lysis. However, little direct evidence has been provided to establish a link between changes in permeability and 2B-induced apoptosis.…”