Department of Biochemistry and Molecular Pharmacology; Program in Chemical Biology; Thompson Lab
Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry | Immune System Diseases | Immunology and Infectious Disease | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Musculoskeletal Diseases
Protein citrullination is a post-translational modification catalyzed by the protein arginine deiminases (PADs). This modification plays a crucial role in the pathophysiology of numerous autoimmune disorders including RA. Recently, there has been a growing interest in investigating physiological regulators of PAD activity to understand the primary cause of the associated disorders. Apart from calcium, it is well-documented that a reducing environment activates the PADs. Although the concentration of thioredoxin (hTRX), an oxidoreductase that maintains the cellular reducing environment, is elevated in RA patients, its contribution toward RA progression or PAD activity has not been explored. Herein, we demonstrate that hTRX activates PAD4. Kinetic characterization of PAD4 using hTRX as the reducing agent yielded parameters that are comparable to those obtained with a routinely used non-physiological reducing agent, e.g., DTT, suggesting the importance of hTRX in PAD regulation under physiological conditions. Furthermore, we show that various hTRX mutants, including redox inactive hTRX variants, are capable of activating PAD4. This indicates a mechanism that does not require oxidoreductase activity. Indeed, we observed non-covalent interactions between PAD4 and hTRX variants, and propose that these redox-independent interactions are sufficient for hTRX-mediated PAD4 activation.
NETosis, PAD4, autoantibodies, citrullination, rheumatoid arthritis, thioredoxin
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Copyright © 2019 Nagar, Tilvawala and Thompson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
DOI of Published Version
Front Immunol. 2019 Feb 19;10:244. doi: 10.3389/fimmu.2019.00244. eCollection 2019. Link to article on publisher's site
Frontiers in immunology
Nagar M, Tilvawala R, Thompson PR. (2019). Thioredoxin Modulates Protein Arginine Deiminase 4 (PAD4)-Catalyzed Citrullination. Open Access Articles. https://doi.org/10.3389/fimmu.2019.00244. Retrieved from https://escholarship.umassmed.edu/oapubs/3772
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This work is licensed under a Creative Commons Attribution 4.0 License.
Biochemical Phenomena, Metabolism, and Nutrition Commons, Biochemistry Commons, Immune System Diseases Commons, Immunology and Infectious Disease Commons, Medicinal Chemistry and Pharmaceutics Commons, Medicinal-Pharmaceutical Chemistry Commons, Musculoskeletal Diseases Commons