The transcription factor FoxP3 can fold into two dimerization states with divergent implications for regulatory T cell function and immune homeostasis

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...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2022-08, Vol.55 (8), p.1354-1369.e8
Main Authors: 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
Format: Article
Language:English
Subjects:
Core Binding Factor Alpha 2 Subunit - genetics
Dimerization
DNA
forkhead
Forkhead Transcription Factors - metabolism
Foxp3
Homeostasis
homodimer
IPEX
Runx1
T-Lymphocytes, Regulatory
transcription factor
Treg
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Summary: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. [Display omitted] •FoxP3 forms a head-to-head (H-H) dimer, instead of a domain-swap dimer•H-H dimerization confers distinct DNA specificity and promotes Runx1 binding•H-H dimerization is unique to Foxp3, providing functional specialization•Disease mutation R337Q causes swap dimerization of FoxP3 and impairs its function FoxP3 is an essential transcription factor for regulatory T cells and overall immunologic homeostasis. We show that the forkhead DNA-binding domains of FoxP3 form a unique head-to-head dimer. This is important for DNA and cofactor binding and provides functional specificity. Furthermore, a disease mutation inducing alternative dimerization impairs Foxp3 function.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2022.07.002