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Journal of Virology, March 2000, p. 2731-2739, Vol. 74, No. 6
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Regulation of Adenovirus Membrane Penetration by the Cytoplasmic Tail of Integrin beta 5dagger

Kena Wang,1 Tinglu Guan,2 David A. Cheresh,1 and Glen R. Nemerow1,*

Departments of Immunology1 and Cell Biology,2 The Scripps Research Institute, La Jolla, California 92037

Received 30 September 1999/Accepted 21 December 1999

Adenovirus (Ad) cell entry involves sequential interactions with host cell receptors that mediate attachment (CAR), internalization (alpha vbeta 3 and alpha vbeta 5), and penetration (alpha vbeta 5) of the endosomal membrane. These events allow the virus to deliver its genome to the nucleus. While integrins alpha vbeta 3 and alpha vbeta 5 both promote Ad internalization into cells, integrin alpha vbeta 5 selectively facilitates Ad-mediated membrane permeabilization and endosome rupture. In the experiments reported herein, we demonstrate that the intracellular domain of the integrin beta 5 subunit specifically regulates Ad-mediated membrane permeabilization and gene delivery. CS-1 melanoma cells expressing a truncated integrin beta 5 or a chimeric (beta 5-beta 3) cytoplasmic tail (CT) supported normal levels of Ad endocytosis but had reduced Ad-mediated gene delivery and membrane permeabilization relative to cells expressing a wild-type integrin beta 5. Thin-section electron microscopy revealed that virion particles were capable of being endocytosed into cells expressing a truncated beta 5CT, but they failed to escape cytoplasmic vesicles and translocate to the nucleus. Site-specific mutagenesis studies suggest that a C-terminal TVD motif in the beta 5CT plays a major role in Ad membrane penetration.

* Corresponding author. Mailing address: Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8072. Fax: (858) 784-8472. E-mail: gnemerow{at}scripps.edu.

dagger Manuscript 12502-IMM of The Scripps Research Institute.

Journal of Virology, March 2000, p. 2731-2739, Vol. 74, No. 6
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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