Intracellular protein modification associated with altered T cell functions in autoimmunity

Area of Science:

• Immunology
• Biochemistry
• Molecular Biology

Background:

• Posttranslational protein modifications significantly impact immune responses.
• Isoaspartyl (isoAsp) modification is a nonenzymatic alteration of aspartic acid residues under physiological conditions.

Purpose of the Study:

• To investigate intracellular isoAsp levels in autoimmune MRL mouse strains compared to nonautoimmune controls.
• To determine the association between isoAsp accumulation and T cell hyperproliferation in autoimmune mice.

Main Methods:

• Quantification of intracellular isoAsp residues in self-proteins from MRL(+/+) , MRL/lpr, NZB/W F(1), and B10.BR mice.
• Analysis of protein isoaspartate O-methyltransferase activity.
• Comparison of isoAsp levels in various tissues and cell types, including erythrocytes, brain, kidney, and T lymphocytes.

Main Results:

• Isoaspartyl content increased and accumulated with age in erythrocytes, brain, kidney, and T lymphocytes of MRL autoimmune mice, unlike in B10.BR or NZB/W mice.
• T cells exhibiting hyperproliferation in MRL mice showed elevated intracellular isoAsp protein levels.
• Protein l-isoaspartate O-methyltransferase activity remained stable with age across all mouse strains.

Conclusions:

• Accumulation of intracellular isoaspartyl proteins is associated with T cell proliferative defects in MRL autoimmune mice.
• This study highlights a potential role for isoAsp modification in the pathogenesis of autoimmune diseases.