Apoptosis plays an important role in the pathogenesis of reovirus encephalitis. Reovirus outer-capsid protein μ1, which functions to penetrate host cell membranes during viral entry, is the primary regulator of apoptosis following reovirus infection. Ectopic expression of full-length and truncated forms of μ1 indicates that the μ1 φ domain is sufficient to elicit a cell death response. To evaluate the contribution of the μ1 φ domain to the induction of apoptosis following reovirus infection, φ mutant viruses were generated by reverse genetics and analyzed for the capacity to penetrate cell membranes and elicit apoptosis. We found that mutations in φ diminish reovirus membrane penetration efficiency by preventing conformational changes that lead to generation of key reovirus entry intermediates. Independent of effects on membrane penetration, amino acid substitutions in φ affect the apoptotic potential of reovirus, suggesting that φ initiates apoptosis subsequent to cytosolic delivery. In comparison to wild-type virus, apoptosis-defective φ mutant viruses display diminished neurovirulence following intracranial inoculation of newborn mice. These results indicate that the φ domain of μ1 plays an important regulatory role in reovirus-induced apoptosis and disease. © 2008 Danthi et al.
Danthi, P., Coffey, C. M., Parker, J. S. L., Abel, T. W., & Dermody, T. S. (2008). Independent regulation of reovirus membrane penetration and apoptosis by the μ1 φ domain. PLoS Pathogens, 4(12). https://doi.org/10.1371/journal.ppat.1000248