Intracellular protein modification associated with altered T cell functions in autoimmunity.
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 F(1) 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.
Yang
Mei-Ling
ML
Section of Rheumatology, Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA.
Doyle
Hester A
HA
Gee
Renelle J
RJ
Lowenson
Jonathan D
JD
Clarke
Steven
S
Lawson
Brian R
BR
Aswad
Dana W
DW
Mamula
Mark J
MJ
D000367:Age Factors; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D049109:Cell Proliferation; D004912:Erythrocytes / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D019463:Mice, Inbred MRL lpr; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase / Q000032:analysis / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D001224:Aspartic Acid; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase