Fas- and Tumor Necrosis Factor-induced Apoptosis Is Inhibited by the Poxvirus crmA Gene Product

doi:10.1074/jbc.270.7.3255

Fas- and Tumor Necrosis Factor-induced Apoptosis Is Inhibited by the Poxvirus crmA Gene Product (*)

From the Department of Pathology and the Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109

^¶ Established Investigator of the American Heart Association. To whom correspondence should be addressed:
Dept. of Pathology, University of Michigan Medical School, 1301 Catherine St., Box 0602, Ann Arbor, MI 48109.
Tel.: 313-747-2921; Fax: 313-764-4308; vishva.dixit{at}med.umich.edu

Abstract

crmA is a cowpox virus gene that encodes a protease inhibitor of the serpin family. The only reported target for the CrmA protein is the cysteine protease interleukin-1β converting enzyme (ICE). ICE, by virtue of its homology to the Caenorhabditis elegans cell death protein Ced-3, has been suggested to play a fundamentally important role in mammalian apoptosis. We hypothesized that a function of crmA may be to inhibit cell death, since a major mechanism of viral clearance is the immune system-mediated induction of apoptosis of infected cells. The tumor necrosis factor receptor and the Fas antigen are two cytokine receptors which, by engaging and activating the death pathway, can eliminate virus-infected cells. Remarkably, crmA was found to be an exceptionally potent inhibitor of apoptosis induced by both these receptors, capable of blocking the cell death program even at pharmacological doses of the death stimulus. Therefore, an important new function for crmA is the inhibition of cytokine-induced apoptosis. Further, the data suggest that a protease, either ICE or a related crmA-inhibitable protein, is a component of the Fas- and tumor necrosis factor-induced cell death pathways.

Footnotes

↵^§ Fellow of the Medical Scientist Training Program. Supported by a Young Scientist M.D./Ph.D. Fellowship from the Life and Health Insurance Medical Research Fund.
↵* This work was supported in part by National Institutes of Health Grant CA61348. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

PCD

programmed cell death

ICE

interleukin-1β converting enzyme

TNF

tumor necrosis factor

CHX

cycloheximide

PBS

phosphate-buffered saline

MTT

(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide).
↵² M. Tewari and V. M. Dixit, unpublished observations.
- Received October 5, 1994.
- Revision received December 14, 1994.