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

Immunity. 2022 Aug 9;55(8):1354-1369.e8. doi: 10.1016/j.immuni.2022.07.002. Epub 2022 Aug 3.

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.

Keywords: Foxp3; IPEX; Runx1; Treg; forkhead; homodimer; transcription factor.

MeSH terms

  • Core Binding Factor Alpha 2 Subunit* / genetics
  • DNA
  • Dimerization
  • Forkhead Transcription Factors / metabolism
  • Homeostasis
  • T-Lymphocytes, Regulatory*

Substances

  • Core Binding Factor Alpha 2 Subunit
  • Forkhead Transcription Factors
  • DNA