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dc.contributor.authorNagar, Mitesh
dc.contributor.authorTilvawala, Ronak
dc.contributor.authorThompson, Paul R
dc.date2022-08-11T08:09:52.000
dc.date.accessioned2022-08-23T16:46:55Z
dc.date.available2022-08-23T16:46:55Z
dc.date.issued2019-02-19
dc.date.submitted2019-05-06
dc.identifier.citation<p>Front Immunol. 2019 Feb 19;10:244. doi: 10.3389/fimmu.2019.00244. eCollection 2019. <a href="https://doi.org/10.3389/fimmu.2019.00244">Link to article on publisher's site</a></p>
dc.identifier.issn1664-3224 (Linking)
dc.identifier.doi10.3389/fimmu.2019.00244
dc.identifier.pmid30853960
dc.identifier.urihttp://hdl.handle.net/20.500.14038/40974
dc.description.abstractProtein 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=30853960&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright © 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.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectNETosis
dc.subjectPAD4
dc.subjectautoantibodies
dc.subjectcitrullination
dc.subjectrheumatoid arthritis
dc.subjectthioredoxin
dc.subjectBiochemical Phenomena, Metabolism, and Nutrition
dc.subjectBiochemistry
dc.subjectImmune System Diseases
dc.subjectImmunology and Infectious Disease
dc.subjectMedicinal Chemistry and Pharmaceutics
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectMusculoskeletal Diseases
dc.titleThioredoxin Modulates Protein Arginine Deiminase 4 (PAD4)-Catalyzed Citrullination
dc.typeJournal Article
dc.source.journaltitleFrontiers in immunology
dc.source.volume10
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=4786&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/3772
dc.identifier.contextkey14438118
refterms.dateFOA2022-08-23T16:46:55Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathoapubs/3772
dc.contributor.departmentThompson Lab
dc.contributor.departmentProgram in Chemical Biology
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages244


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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.
Except where otherwise noted, this item's license is described as 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.