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in Lupus T Cells through HRES-1/Rab4-Regulated Lysosomal Degradation1
* Division of Rheumatology, Department of Medicine,
Department of Microbiology and Immunology, and
Genetics Core, Department of Neuroscience and Physiology, State University of New York, Syracuse, NY 13210;
Hospital for Special Surgery, New York, NY 10021; and
¶ Department of Biochemistry, University of Frankfurt, Frankfurt, Germany
Persistent mitochondrial hyperpolarization (MHP) and enhanced calcium fluxing underlie aberrant T cell activation and death pathway selection in systemic lupus erythematosus. Treatment with rapamycin, which effectively controls disease activity, normalizes CD3/CD28-induced calcium fluxing but fails to influence MHP, suggesting that altered calcium fluxing is downstream or independent of mitochondrial dysfunction. In this article, we show that activity of the mammalian target of rapamycin (mTOR), which is a sensor of the mitochondrial transmembrane potential, is increased in lupus T cells. Activation of mTOR was inducible by NO, a key trigger of MHP, which in turn enhanced the expression of HRES-1/Rab4, a small GTPase that regulates recycling of surface receptors through early endosomes. Expression of HRES-1/Rab4 was increased in CD4+ lupus T cells, and in accordance with its dominant impact on the endocytic recycling of CD4, it was inversely correlated with diminished CD4 expression. HRES-1/Rab4 overexpression was also inversely correlated with diminished TCR
protein levels. Pull-down studies revealed a direct interaction of HRES-1/Rab4 with CD4 and TCR. Importantly, the deficiency of the TCR chain and of Lck and the compensatory up-regulation of Fc
RI
and Syk, which mediate enhanced calcium fluxing in lupus T cells, were reversed in patients treated with rapamcyin in vivo. Knockdown of HRES-1/Rab4 by small interfering RNA and inhibitors of lysosomal function augmented TCR protein levels in vitro. The results suggest that activation of mTOR causes the loss of TCR in lupus T cells through HRES-1/Rab4-dependent lysosomal degradation.
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.
1 This research was supported by National Institutes of Health Grants R01 AI-048079 and AI-072648, the Alliance for Lupus Research, and the Central New York Community Foundation.
2 Address correspondence and reprint requests to Dr. Andras Perl, Division of Rheumatology, Department of Medicine, State University of New York, 750 East Adams Street, Syracuse, NY 13210. E-mail address: perla{at}upstate.edu
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; FKBP12, 12-kDa FK506-binding protein; L-NMMA, L-NG-monomethyl arginine citrate; LTR, Lysotracker Red; MHP, mitochondrial hyperpolarization; mTOR, mammalian target of rapamycin; NOSIP, NO synthase inhibitory protein; eNOS, endothelial NO synthase; RA, rheumatoid arthritis; S6K, S6 kinase; siRNA, small interfering RNA; SOD2, superoxide dismutase 2; TAL, transaldolase; TFR, transferrin receptor; VDAC1, voltage-dependent anion channel 1; 
m, mitochondrial transmembrane potential.
4 The online version of this article contains supplemental material.
This article has been cited by other articles:
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  M. Blank, Y. Shoenfeld, and A. Perl Cross-talk of the environment with the host genome and the immune system through endogenous retroviruses in systemic lupus erythematosus Lupus, November 1, 2009; 18(13): 1136 - 1143. [Abstract] [PDF]
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