Isoaspartyl Posttranslational Modification In Drug‐Induced Lupus

Abstract

Autoimmune responses, such as those in lupus, rheumatoid arthritis, and multiple sclerosis, frequently target self proteins that undergo post‐translational protein modifications. We have previously identified one modification, termed isoaspartyl (isoAsp), that triggers autoimmunity in murine models of lupus. Isoaspartyl modification is a non‐enzymatic, spontaneous event that occurs at physiologic pH and temperature in all cells. We have demonstrated that intracellular levels of isoAsp modified proteins are significantly higher and accumulate with age in spontaneous MRL lupus‐prone mice. IsoAsp modification contributes to T cell hyperproliferation via the Erk 1/2 pathway and is coincident with the onset of autoantibodies and pathology in the MRL mouse. Within cells, aberrant isoAsp self‐proteins are normally repaired by protein L‐isoaspartyl methyltransferase (PIMT) via methylation reactions that utilize S‐adenosyl‐methionine (SAM) as a methyl donor. Our recent studies suggest that isoAsp modification may also be important in the onset of drug‐induced lupus. The well‐known lupus‐inducing drugs, procainamide and hydralazine, both are inhibitors of DNA methylation similarly utilize SAM in the cell. We examined the effects of lupus‐inducing drugs on PIMT repair, isoaspartyl protein accumulation, and lymphocyte functions. We now demonstrate that PIMT repair activity is inhibited by hydralazine in dose‐dependent manner leading to increased isoAsp protein modification and T cell hyperproliferation similar to that observed in the MRL mouse. These data suggest that the balance between isoAsp formation and its repair by PIMT is also relevant to T cell function in drug‐induced lupus. [Grant support: Arthritis Foundation Postdoctoral Fellowship (MLY) and NIH‐AI‐48120 (MJM)]