The transcription factor FoxP3 can fold into two dimerization states with divergent implications for regulatory T cell function and immune homeostasis Journal Article
| Authors: | Leng, F.; Zhang, W.; Ramirez, R. N.; Leon, J.; Zhong, Y.; Hou, L.; Yuki, K.; van der Veeken, J.; Rudensky, A. Y.; Benoist, C.; Hur, S. |
| Article Title: | The transcription factor FoxP3 can fold into two dimerization states with divergent implications for regulatory T cell function and immune homeostasis |
| 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. © 2022 The Author(s) |
| Keywords: | genetics; forkhead transcription factors; metabolism; transcription factor; regulatory t lymphocyte; dna; t-lymphocytes, regulatory; dimerization; homeostasis; forkhead transcription factor; core binding factor alpha 2 subunit; transcription factor runx1; foxp3; homodimer; forkhead; ipex; runx1; treg |
| Journal Title: | Immunity |
| Volume: | 55 |
| Issue: | 8 |
| ISSN: | 1074-7613 |
| Publisher: | Cell Press |
| Date Published: | 2022-08-09 |
| Start Page: | 1354 |
| End Page: | 1369.e8 |
| Language: | English |
| DOI: | 10.1016/j.immuni.2022.07.002 |
| PUBMED: | 35926508 |
| PROVIDER: | scopus |
| PMCID: | PMC9907729 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2022 -- Source: Scopus |
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