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The transcription factor FoxP3 can fold into two dimerization states with divergent implications for regulatory T cell function and immune homeostasis.
Leng, Fangwei; Zhang, Wenxiang; Ramirez, Ricardo N; Leon, Juliette; Zhong, Yi; Hou, Lifei; Yuki, Koichi; van der Veeken, Joris; Rudensky, Alexander Y; Benoist, Christophe; Hur, Sun.
Afiliação
  • Leng F; Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • Zhang W; Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • Ramirez RN; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Leon J; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Zhong Y; Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA; Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Hou L; Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • Yuki K; Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • van der Veeken J; Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria.
  • Rudensky AY; Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Benoist C; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Hur S; Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: sun.hur@crystal.harvard.edu.
Immunity ; 55(8): 1354-1369.e8, 2022 08 09.
Article em En | MEDLINE | ID: mdl-35926508
ABSTRACT
FoxP3 is an essential transcription factor (TF) for immunologic homeostasis, but how it utilizes the common forkhead DNA-binding domain (DBD) to perform its unique function remains poorly understood. We here demonstrated that unlike other known forkhead TFs, FoxP3 formed a head-to-head dimer using a unique linker (Runx1-binding region [RBR]) preceding the forkhead domain. Head-to-head dimerization conferred distinct DNA-binding specificity and created a docking site for the cofactor Runx1. RBR was also important for proper folding of the forkhead domain, as truncation of RBR induced domain-swap dimerization of forkhead, which was previously considered the physiological form of FoxP3. Rather, swap-dimerization impaired FoxP3 function, as demonstrated with the disease-causing mutation R337Q, whereas a swap-suppressive mutation largely rescued R337Q-mediated functional impairment. Altogether, our findings suggest that FoxP3 can fold into two distinct dimerization states head-to-head dimerization representing functional specialization of an ancient DBD and swap dimerization associated with impaired functions.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos T Reguladores / Subunidade alfa 2 de Fator de Ligação ao Core Idioma: En Revista: Immunity Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos T Reguladores / Subunidade alfa 2 de Fator de Ligação ao Core Idioma: En Revista: Immunity Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos