Death by Viroporin

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v i r a l pat h o g e n e s i S Death by viroporin

A paper recently published in Cellular Microbiology reports that viroporins of hepatitis C virus (HCV), poliovirus and other animal RNA viruses induce apoptosis in host cells. Viroporins are present in tiny amounts in the virions of most enveloped animal RNA viruses. Examples include Sindbis virus 6K protein, influenza A virus M2 protein, poliovirus 2B and 3A proteins, mouse hepatitis virus E protein, HIV Vpu and severe acute respiratory syndrome coronavirus E protein. These small (around 100 amino acids), extremely hydrophobic proteins oligomerize to form pores in host-cell membranes through which Mouse hepatitis virus E protein Taken together, this evidence led the viruses can bud. Viroporins contrib- and HIV Vpu had both previously authors to propose that viroporins ute to the pathology of disease by been shown to induce apoptosis, so activate apoptosis by the mitochon- altering membrane permeability and Madan and colleagues looked for drial pathway. These findings are all disrupting ion homeostasis in cells. characteristic signatures of apop- the more surprising given that polio- Inspection of the structural tosis in BHK cells that expressed virus proteins 2B and 3A suppress features and hydrophobicity viroporins. All the viroporins apoptosis in HeLa cells at low levels. It profiles of small proteins encoded induced chromatin condensation, is possible that viroporins have differ- by HCV revealed two candidate nuclear DNA fragmentation and ent effects depending on the level of viroporins, NS4A and p7. Using activation of the key apoptosis expression and/or the host-cell type. an expression system that was enzyme caspase 3, but the strongest The induction of apoptosis in based on Sindbis virus to mimic pro-apoptotic response was induced host cells by viruses is common and the expression of viroporins dur- by HCV NS4A and poliovirus could aid virus spread. The next step ing infection, the comparative protein 2B. in understanding the intriguing links effects of selected viroporins Another intriguing link between between viroporins and apoptosis — Sindbis virus 6K protein, influ- viroporins and apoptosis is the will be to unravel the mechanisms by enza A virus M2 protein, polio- reported association of a fraction of which viroporins trigger apoptotic virus 2B and 3A proteins, mouse HCV p7 and NS4A proteins with pathways and demonstrate that these hepatitis virus E protein and HCV mitochondria. The authors showed findings are relevant during infection. p7 and NS4A proteins — on baby that HCV NS4A and poliovirus 2B Susan Jones hamster kidney (BHK) cells was colocalized with mitochondria and evaluated. On expression, each that expression of other viroporins Original Research Paper Madan, V., protein that was tested altered altered mitochondrial morphology Castello, A. & Carrasco, L. Viroporins from RNA membrane permeability, which and distribution. Notably, the expres- viruses induce caspase-dependent apoptosis. Cell. Microbiol. 25 Oct 2007 (doi 10.1111/j.1462- confirmed that these proteins are sion of all viroporins led to the release 5822.2007.01057.x) bona fide viroporins. of cytochrome c from mitochondria.