Citrullination Inhibits SERPIN Activity

The Protein Arginine Deiminases (PADs) hydrolyze arginine residues to form citrulline. This post‐translational modification, termed citrullination, is upregulated in numerous cancers and autoimmune disorders including Rheumatoid Arthritis (RA), lupus, and Alzheimer's disease. While these enzymes are important regulators of gene transcription, the full spectrum of biological activities is relatively underexplored. Recently, the Thompson group reported the development of a suite of probes to detect and isolate citrullinated proteins. These probes are premised on the chemo‐selective reaction of citrulline with phenylglyoxals under acidic conditions. Herein, I will discuss our development of these probes and their use to uncover the RA citrullinome. Specifically, these probes were used to identify the citrullinated proteins present in RA serum, RA synovial fluid, and RA synovial tissue. The proteins identified from these analyses include >150 proteins that were previously not known to be citrullinated. Moreover, these proteins include numerous metabolic enzymes and serine protease inhibitors (SERPINs). Citrullination inactivates the activity of a subset of these proteins, including nicotinamide N‐methyltransferase and numerous P1‐arginine containing SERPINs (e.g., C1 inhibitor, anti‐thrombin, and anti‐plasmin). The ability to inhibit SERPIN activity is highly significant because it suggests PAD release within the RA synovium leads to SERPIN citrullination with a consequent increase in protease activity, thereby activating multiple processes including tissue remodeling, altered blood coagulation, and the activation of the complement cascade. Support or Funding Information This work was supported in part by NIH grant GM109767 to P.R.T. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .