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dc.contributor.authorSun, Bo
dc.contributor.authorChang, Hui-Hsin
dc.contributor.authorSalinger, Ari J.
dc.contributor.authorTomita, Beverly
dc.contributor.authorBawadekar, Mandar
dc.contributor.authorHolmes, Caitlyn L.
dc.contributor.authorShelef, Miriam A.
dc.contributor.authorWeerapana, Eranthie
dc.contributor.authorThompson, Paul R
dc.contributor.authorHo, I-Cheng
dc.date2022-08-11T08:09:54.000
dc.date.accessioned2022-08-23T16:48:28Z
dc.date.available2022-08-23T16:48:28Z
dc.date.issued2019-11-14
dc.date.submitted2019-12-11
dc.identifier.citation<p>JCI Insight. 2019 Nov 14;4(22). pii: 129687. doi: 10.1172/jci.insight.129687. <a href="https://doi.org/10.1172/jci.insight.129687">Link to article on publisher's site</a></p>
dc.identifier.issn2379-3708 (Linking)
dc.identifier.doi10.1172/jci.insight.129687
dc.identifier.pmid31723060
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41278
dc.description.abstractDysregulated citrullination, a unique form of posttranslational modification catalyzed by the peptidylarginine deiminases (PADs), has been observed in several human diseases, including rheumatoid arthritis. However, the physiological roles of PADs in the immune system are still poorly understood. Here, we report that global inhibition of citrullination enhances the differentiation of type 2 helper T (Th2) cells but attenuates the differentiation of Th17 cells, thereby increasing the susceptibility to allergic airway inflammation. This effect on Th cells is due to inhibition of PAD2 but not PAD4. Mechanistically, PAD2 directly citrullinates GATA3 and RORgammat, 2 key transcription factors determining the fate of differentiating Th cells. Citrullination of R330 of GATA3 weakens its DNA binding ability, whereas citrullination of 4 arginine residues of RORgammat strengthens its DNA binding. Finally, PAD2-deficient mice also display altered Th2/Th17 immune response and heightened sensitivity to allergic airway inflammation. Thus, our data highlight the potential and caveat of PAD2 as a therapeutic target of Th cell-mediated diseases.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31723060&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1172/jci.insight.129687
dc.subjectAdaptive immunity
dc.subjectAllergy
dc.subjectAutoimmunity
dc.subjectImmunology
dc.subjectT cells
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemical Phenomena, Metabolism, and Nutrition
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectImmune System Diseases
dc.subjectImmunity
dc.subjectImmunopathology
dc.subjectImmunoprophylaxis and Therapy
dc.subjectMusculoskeletal Diseases
dc.titleReciprocal regulation of Th2 and Th17 cells by PAD2-mediated citrullination
dc.typeJournal Article
dc.source.journaltitleJCI insight
dc.source.volume4
dc.source.issue22
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4065
dc.identifier.contextkey15973600
html.description.abstract<p>Dysregulated citrullination, a unique form of posttranslational modification catalyzed by the peptidylarginine deiminases (PADs), has been observed in several human diseases, including rheumatoid arthritis. However, the physiological roles of PADs in the immune system are still poorly understood. Here, we report that global inhibition of citrullination enhances the differentiation of type 2 helper T (Th2) cells but attenuates the differentiation of Th17 cells, thereby increasing the susceptibility to allergic airway inflammation. This effect on Th cells is due to inhibition of PAD2 but not PAD4. Mechanistically, PAD2 directly citrullinates GATA3 and RORgammat, 2 key transcription factors determining the fate of differentiating Th cells. Citrullination of R330 of GATA3 weakens its DNA binding ability, whereas citrullination of 4 arginine residues of RORgammat strengthens its DNA binding. Finally, PAD2-deficient mice also display altered Th2/Th17 immune response and heightened sensitivity to allergic airway inflammation. Thus, our data highlight the potential and caveat of PAD2 as a therapeutic target of Th cell-mediated diseases.</p>
dc.identifier.submissionpathoapubs/4065
dc.contributor.departmentThompson Lab
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology


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