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Journal of Virology, October 2002, p. 9920-9933, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9920-9933.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Strategy for Nonenveloped Virus Entry: a Hydrophobic Conformer of the Reovirus Membrane Penetration Protein µ1 Mediates Membrane Disruption{dagger}

Kartik Chandran,1 Diane L. Farsetta,2,{ddagger} and Max L. Nibert1*

Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115,1 Cell and Molecular Biology Program, University of Wisconsin—Madison, Madison, Wisconsin 537062

Received 2 April 2002/ Accepted 26 June 2002

The mechanisms employed by nonenveloped animal viruses to penetrate the membranes of their host cells remain enigmatic. Membrane penetration by the nonenveloped mammalian reoviruses is believed to deliver a partially uncoated, but still large (~70-nm), particle with active transcriptases for viral mRNA synthesis directly into the cytoplasm. This process is likely initiated by a particle form that resembles infectious subvirion particles (ISVPs), disassembly intermediates produced from virions by proteolytic uncoating. Consistent with that idea, ISVPs, but not virions, can induce disruption of membranes in vitro. Both activities ascribed to ISVP-like particles, membrane disruption in vitro and membrane penetration within cells, are linked to N-myristoylated outer-capsid protein µ1, present in 600 copies at the surfaces of ISVPs. To understand how µ1 fulfills its role as the reovirus penetration protein, we monitored changes in ISVPs during the permeabilization of red blood cells induced by these particles. Hemolysis was preceded by a major structural transition in ISVPs, characterized by conformational change in µ1 and elution of fibrous attachment protein {sigma}1. The altered conformer of µ1 was required for hemolysis and was markedly hydrophobic. The structural transition in ISVPs was further accompanied by derepression of genome-dependent mRNA synthesis by the particle-associated transcriptases. We propose a model for reovirus entry in which (i) primed and triggered conformational changes, analogous to those in enveloped-virus fusion proteins, generate a hydrophobic µ1 conformer capable of inserting into and disrupting cell membranes and (ii) activation of the viral particles for membrane interaction and mRNA synthesis are concurrent events. Reoviruses provide an opportune system for defining the molecular details of membrane penetration by a large nonenveloped animal virus.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115. Phone: (617) 432-4829. Fax: (617) 738-7664. E-mail: mnibert{at}hms.harvard.edu.

{dagger} This paper is dedicated to the memory of Lakshmi Chandran.

{ddagger} Present address: ETAN Field Office, Social Justice Center, Madison, WI 53703.

Journal of Virology, October 2002, p. 9920-9933, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9920-9933.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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