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Journal of Virology, June 2004, p. 6304-6312, Vol. 78, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.12.6304-6312.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

PB1-F2, an Influenza A Virus-Encoded Proapoptotic Mitochondrial Protein, Creates Variably Sized Pores in Planar Lipid Membranes

A. N. Chanturiya,1 G. Basañez,2 U. Schubert,3,4 P. Henklein,5 J. W. Yewdell,6 and J. Zimmerberg1*

Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development,1 Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,6 Heinrich-Pette-Institute of Experimental Virology and Immunology, University of Hamburg, Hamburg,3 Institute of Clinical and Molecular Virology, University of Erlangen-Nürnberg, Erlangen,4 Institute of Biochemistry, Humboldt University, Berlin, Germany,5 Unidad de Biofisica (Centro Mixto UPV/EHU-CSIC), Universidad del Pais Vasco (UPV/EHU), 48080 Bilbao, Spain2

Received 30 October 2003/ Accepted 12 February 2004

A frameshifted region of the influenza A virus PB1 gene encodes a novel protein, termed PB1-F2, a mitochondrial protein that can induce cell death. Many proapoptotic proteins are believed to act at the mitochondrial outer membrane to form an apoptotic pore with lipids. We studied the interaction of isolated, synthetic PB1-F2 (sPB1-F2) peptide with planar phospholipid bilayer membranes. The presence of nanomolar concentrations of peptide in the bathing solution induced a transmembrane conductance that increased in a potential-dependent manner. Positive potential on the side of protein addition resulted in a severalfold increase in the rate of change of membrane conductance. sPB1-F2-treated membranes became permeable to monovalent cations, chloride, and to a lesser extent, divalent ions. Despite various experimental conditions, we did not detect the distinctive conductance levels typical of large, stable pores, protein channels, or even pores that are partially proteinaceous. Rather, membrane conductance induced by sPB1-F2 fluctuated and visited almost all conductance values. sPB1-F2 also dramatically decreased bilayer stability in an electric field, consistent with a decrease in the line tension of a lipidic pore. Since similar membrane-destabilizing profiles are seen with proapoptotic proteins (e.g., Bax) and the cytoplasmic helix of human immunodeficiency virus gp41, we suggest that the basis for sPB1-F2-induced cell death may be the permeabilization and destabilization of mitochondrial membranes, leading to macromolecular leakage and apoptosis.

* Corresponding author. Mailing address: Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10D14, Bethesda, MD 20892-1855. Phone: (301) 496-6571. Fax: (301) 402-0263. E-mail: joshz{at}helix.nih.gov.

Journal of Virology, June 2004, p. 6304-6312, Vol. 78, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.12.6304-6312.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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