An Unexpected Functional Link between Lysosomal Thiol Reductase and Mitochondrial Manganese Superoxide Dismutase*
- ‡Department of Microbiology and Immunology, Georgetown University, Washington, D. C. 20057 and the §Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, D. C. 20010-2970
- 1 To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Georgetown University Medical Center, 3900 Reservoir Rd. NW, Med/Dent C301, Washington, D. C. 20057. Tel.: 202-687-3749; Fax: 202-687-1800; E-mail: mam254{at}georgetown.edu.
Abstract
Gamma interferon-inducible thiol reductase (GILT) is an enzyme involved in the initial steps of antigen processing and presentation. Recently we have shown that GILT is also expressed in mouse T cells, where it exerts an inhibitory role on T cell activation. In this study, we identified mitochondrial manganese superoxide dismutase (SOD2) as one of the key intermediaries affected by GILT expression in fibroblasts. Expression and activity of SOD2 is reduced in the absence of GILT because of reduced SOD2 protein stability. The forced increase in SOD2 expression in the absence of GILT restores fibroblast proliferation to wild-type levels. Thus, GILT appears to have a fundamental role in cellular proliferation mediated through its influence on SOD2 protein activity and expression.
Footnotes
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↵2 The abbreviations used are: GILT, gamma interferon-inducible lysosomal thiol reductase; WT, wild type; SOD2, superoxide dismutase 2; ROS, reactive oxygen species; EGF, epidermal growth factor; FBS, fetal bovine serum; MF, mouse fibroblast cell line; PMF, primary mouse fibroblast; DHE, dihydroethidium; PBS, phosphate-buffered saline; DCF-DA, 2′,7′-dichlorodihydrofluorescein diacetate; NRF, nuclear respiratory factor.
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↵3 M. Maric, unpublished observations.
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↵* This work was supported by American Heart Association Scientist Development Grant 0535032N. 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.
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The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.
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- Received November 1, 2007.
- Revision received January 16, 2008.
- The American Society for Biochemistry and Molecular Biology, Inc.
