Proust’s imagination and childhood memories were triggered by the smell of his grandmother’s madeleines; my memories today were triggered by a single word, citrulline, an amino acid first extracted from watermelons. Just seeing “citrulline” in a table of contents brought back memories of the urea cycle, epidermal proteins containing citrulline, and my testing amino acids as inhibitors of the epidermal transglutaminase. In the past and still today, I am obsessed with post-translational modification of proteins, especially those occurring in the epidermis. Obsessions do not weaken with time, they may even grow stronger. Citrulline, an amino acid of the urea cycle, is present as a free amino acid at high levels in the epidermis. The role of arginine and the urea cycle amino acid was discussed earlier in this space. Citrulline modifications of protein-bound arginine are in structural proteins in keratinized tissues and are catalyzed by peptidylarginine deaminases. After those findings, autoantibodies to citrullinated proteins were found to be useful biomarkers for rheumatoid arthritis. I remember looking for citrullinated autoantibodies about ten years ago in some epidermal autoimmune diseases. No results — and that mini-experiment was confined to that large group of unpublished studies many researchers keep on a high shelf in a dark back closet.
Then an article in Science Translational Medicine (Romero et al Oct 30) jogged my citrulline memories. Cultured synovial cells treated with perforin or the membrane attack complex rapidly citrullinated multiple synovial proteins. Not one, multiple proteins. Since the peptidylarginine deaminases catalyzing the arginine to citrulline conversion require levels of calcium much higher than those found intracellularly, there are still mechanistic questions to be resolved in this system. Citrulline has reentered my life; my past is not buried as deeply as I thought. I was happy thinking about citrulline after so many years, and, like the urea cycle, what goes around comes around.
Romero V, Fert-Bober J, Nigrovic PA, et al. Immune-Mediated Pore-Forming Pathways Induce Cellular Hypercitrullination and Generate Citrullinated Autoantigens in Rheumatoid Arthritis. Sci Transl Med doi:10.1126/scitranslmed.3006869