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Journal of Virology, September 2006, p. 8739-8744, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00791-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Murine Polyomavirus Requires the Endoplasmic Reticulum Protein Derlin-2 To Initiate Infection

Brendan N. Lilley ,{dagger},{ddagger} Joanna M. Gilbert,{dagger} Hidde L. Ploegh,§ and Thomas L. Benjamin*

Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115

Received 18 April 2006/ Accepted 9 June 2006

The pathways by which viruses enter cells are diverse, but in all cases, infection necessitates the transfer of the viral genome across a cellular membrane. Polyomavirus (Py) particles, after binding to glycolipid and glycoprotein receptors at the cell surface, are delivered to the lumen of the endoplasmic reticulum (ER). The nature and extent of virus disassembly in the ER, how the viral genome is transported to the cytosol and subsequently to the nucleus, and whether any cellular proteins are involved are not known. Here, we identify an ER-resident protein, Derlin-2, a factor implicated in the removal of misfolded proteins from the ER for cytosolic degradation, as a component of the machinery required for mouse Py to establish an infection. Inhibition of Derlin-2 function by expression of either a dominant-negative form of Derlin-2 or a short hairpin RNA that reduces Derlin-2 levels blocks Py infection by 50 to 75%. The block imposed by Derlin-2 inhibition occurs after the virus reaches the ER and can be bypassed by the introduction of Py DNA into the cytosol. These findings suggest a mode of Py entry that involves cytosolic access via the quality control machinery in the ER.

* Corresponding author. Mailing address: Department of Pathology, NRB-939-I, 77 Avenue Louis Pasteur, Boston, MA 02115. Phone: (617) 432-1960. Fax: (617) 432-2689. E-mail: thomas_benjamin{at}hms.harvard.edu.

{dagger} B.N.L. and J.M.G. contributed equally to this work.

{ddagger} Present address: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138.

§ Present address: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.

Journal of Virology, September 2006, p. 8739-8744, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00791-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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