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While FOXP family members have been identified as co-regulators of NFAT1, the involvement of other FOX family proteins has remained mechanistically obscure. Here, we solved three crystal structures of NFAT1\u2013RHR\/FOXC2\u2013DBD\/ARRE DNA ternary complexes and uncovered an unexpected mode of transcriptional repression mediated by FOXC2 through direct, DNA-facilitated binding to the V-shaped groove of NFAT1\u2019s Rel-homology region (RHR). Biochemical assays revealed that DNA enhanced FOXC2\u2013NFAT1 interaction by more than five-fold, supporting a model in which DNA acts as a structural co-factor that promotes complex formation. Mutational disruption of the FOXC2\u2013NFAT1 interface impaired complex assembly and abrogated transcriptional repression. Functional assays further confirmed that FOXC2 suppressed NFAT1-driven transcription of multiple cytokines and chemokines, including IL2, TNF, CXCL5, and CCL2. Notably, this repressive mechanism was found to extend to other FOX proteins (FOXI1, FOXO1, and FOXK1), suggesting a broader paradigm of FOX\u2013NFAT1 interaction. Our study defined a previously unrecognized FOX-mediated transcriptional repression mechanism and provides a structural framework for NFAT inhibition by FOX proteins, offering novel insights into the transcriptional regulation of immune-related genes.<\/jats:p>","DOI":"10.1093\/nar\/gkag367","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T11:40:55Z","timestamp":1775821255000},"source":"Crossref","is-referenced-by-count":2,"title":["FOXC2 represses NFAT1-dependent transcription through a DNA-facilitated protein\u2013protein interaction"],"prefix":"10.1093","volume":"54","author":[{"given":"Xiaojuan","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University , Changsha, Hunan 410008 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sipeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Xiangya Hospital, Central South University , Changsha 410008 Hunan ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitong","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Xiangyang No. 1 People\u2019s Hospital, Hubei University of Medicine , Xiangyang 441000 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University , Changsha, Hunan 410008 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueru","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University , Changsha, Hunan 410008 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyan","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University , Changsha, Hunan 410008 ,","place":["China"]},{"name":"Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University , Changsha 410078 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, The First Affiliated Hospital of University of South China , Hengyang, Hunan 421001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huajun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University , Changsha, Hunan 410008 ,","place":["China"]},{"name":"Department of Ultrasonic Imaging, Xiangya Hospital, Central South University , Changsha 410008 Hunan ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hudie","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University , Changsha, Hunan 410008 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University , Changsha, Hunan 410008 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingzhi","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University , Changsha, Hunan 410008 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Molecular and Computational Biology, Department of Biological Sciences, University of Southern California , Los Angeles, CA 90089 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalan","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University , Changsha, Hunan 410008 ,","place":["China"]},{"name":"Department of Ultrasonic Imaging, Xiangya Hospital, Central South University , Changsha 410008 Hunan 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