FOXP3 snatches transcription factors depending on the context

Abstract

FOXP3 hijacks DNA-binding proteins to regulate gene expression. In this issue of JEM, He et al. (https://doi.org/10.1084/jem.20232068) propose a dynamic model in which FOXP3 associates with DNA-binding proteins to regulate Treg cell function in response to environmental cues.

Insights from Lisa Schmidleithner, Philipp Stüve, and Markus Feuerer.

Environmental cues direct FOXP3 binding partners in Treg cells. In resting lymph nodes, FOXP3 forms a complex with ETS family members, while during activation, FOXP3 forms a complex with AP-1 family members such as BATF. IL-2 stimulation induces FOXP3 binding to STAT5 while TCR stimulation induces FOXP3–NFAT binding. We speculate that under homeostatic conditions in the tissue, FOXP3 interacts with BATF to bind to DNA. Under different conditions in the tissue, such as under inflammation or in the tumor environment, external cues may influence the FOXP3 complex to include other DNA-binding proteins such as other AP-1 family members (e.g., JUNB) or yet undefined transcription factors (Factor X).