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Intracellular Protein Modification Associated with Altered T Cell Functions in Autoimmunity¹

Mei-Ling Yang^*, Hester A. Doyle^*, Renelle J. Gee^*, Jonathan D. Lowenson, Steven Clarke, Brian R. Lawson, Dana W. Aswad and Mark J. Mamula^2,*

^* Section of Rheumatology, Department of Medicine, Yale University School of Medicine, New Haven, CT 06520; Department of Chemistry and Biochemistry, Molecular Biology Institute, University of California, Los Angeles, CA 90095; Diazyme Laboratories Division, General Atomics, San Diego, CA; and Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697

Posttranslational protein modifications influence a number of immunologic responses ranging from intracellular signaling to protein processing and presentation. One such modification, termed isoaspartyl (isoAsp), is the spontaneous nonenzymatic modification of aspartic acid residues occurring at physiologic pH and temperature. In this study, we have examined the intracellular levels of isoAsp residues in self-proteins from MRL^+/+, MRL/lpr, and NZB/W F₁ mouse strains compared with nonautoimmune B10.BR mice. In contrast to control B10.BR or NZB/W mice, the isoAsp content in MRL autoimmune mice increased and accumulated with age in erythrocytes, brain, kidney, and T lymphocytes. Moreover, T cells that hyperproliferate to antigenic stimulation in MRL mice also have elevated intracellular isoAsp protein content. Protein L-isoaspartate O-methyltransferase activity, a repair enzyme for isoAsp residues in vivo, remains stable with age in all strains of mice. These studies demonstrate a role for the accumulation of intracellular isoAsp proteins associated with T cell proliferative defects of MRL autoimmune mice.

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 work was supported by National Institutes of Health Grants AI-48120 (to M.J.M.) NS-17269 (to D.W.A.), GM-026020 (to S.C.), and AG-18000 (to S.C.), and by an Arthritis Foundation Postdoctoral Fellowship (to M.-L.Y.).

² Address correspondence and reprint requests to Dr. Mark J. Mamula, Yale University School of Medicine, P.O. Box 208031, 300 Cedar Street, New Haven, CT 06520-8031. E-mail address: mark.mamula{at}yale.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; isoAsp, isoaspartyl; PIMT, protein L-isoaspartate O-methyltransferase; snRNP, small nuclear ribonucleoprotein particle; PCC, pigeon cytochrome c; CD62L, CD62 ligand.

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				J. X. Zhu, H. A. Doyle, M. J. Mamula, and D. W. Aswad Protein Repair in the Brain, Proteomic Analysis of Endogenous Substrates for Protein L-Isoaspartyl Methyltransferase in Mouse Brain J. Biol. Chem., November 3, 2006; 281(44): 33802 - 33813. [Abstract] [Full Text] [PDF]