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J. Biol. Chem., Vol. 279, Issue 10, 8547-8557, March 5, 2004

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Cathepsin S Supports Acid-independent Infection by Some Reoviruses^*

Joseph W. Golden¶, Jessica A. Bahe, William T. Lucas||**, Max L. Nibert||, and Leslie A. Schiff

From the Department of Microbiology, University of Minnesota, Minneapolis, Minnesota 55455 and the ^||Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115

In murine fibroblasts, efficient proteolysis of reovirus outer capsid protein 3 during cell entry by virions requires the acid-dependent lysosomal cysteine protease cathepsin L. The importance of cathepsin L for infection of other cell types is unknown. Here we report that the acid-independent lysosomal cysteine protease cathepsin S mediates outer capsid processing in macrophage-like P388D cells. P388D cells supported infection by virions of strain Lang, but not strain c43. Genetic studies revealed that this difference is determined by S4, the viral gene segment that encodes 3. c43-derived subvirion particles that lack 3 replicated normally in P388D cells, suggesting that the difference in infectivity of Lang and c43 virions is at the level of 3 processing. Infection of P388D cells with Lang virions was inhibited by the broad spectrum cysteine protease inhibitor trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane but not by NH₄Cl, which raises the endocytic pH and thereby inhibits acid-dependent proteases such as cathepsins L and B. Outer capsid processing and infection of P388D cells with Lang virions were also inhibited by a cathepsin S-specific inhibitor. Furthermore, in the presence of NH₄Cl, cell lines engineered to express cathepsin S supported infection by Lang, but not c43, virions. Our results thus indicate that differences in susceptibility to cathepsin S-mediated 3 processing are responsible for strain differences in reovirus infection of macrophage-like P388D cells and other cathepsin S-expressing cells. Additionally, our data suggest that the acid dependence of reovirus infections of most other cell types may reflect the low pH requirement for the activities of most other lysosomal proteases rather, than some other acid-dependent aspect of cell entry.

Received for publication, September 3, 2003 , and in revised form, December 9, 2003.

^* This work was supported in part by National Institutes of Health Grants AI-45990 (to L. A. S.) and AI-46440 (to M. L. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This paper is dedicated to our mentor and friend Bernie Fields.

These authors contributed equally to this work.

^¶ Supported by National Institutes of Health Training Grant 2T32 AI-0742.

^** Present address: Apptec, 1667 Davis St., Camden, NJ 08104.

To whom correspondence should be addressed: Dept. of Microbiology, University of Minnesota, Mayo Mail Code 196, 420 Delaware St., S.E., Minneapolis, MN 55455. Tel.: 612-624-9933; Fax: 612-626-0623. E-mail: schiff{at}lenti.med.umn.edu.

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