Independent Regulation of Reovirus Membrane Penetration and Apoptosis by the μ1 φ Domain

PLoS Pathogens

Ty W. Abel¹  John S. L. Parker¹  Terence S. Dermody²  Pranav Danthi³  Caroline M. Coffey⁴ 

[1] Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America;Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America;Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America;Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America

关键词: Apoptosis;    Cell membranes;    Transcription factors;    Intracellular membranes;    L929 cells;    Viral replication;    Central nervous system;    293T cells;   

DOI  :  10.1371/journal.ppat.1000248

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY