Immune regulation by histone deacetylases: a focus on the alteration of FOXP3 activity

Abstract

Several histone deacetylases (HDACs) are involved in the regulation of forkhead box protein P3 (FOXP3) expression and function by affecting features of FOXP3 protein stability. FOXP3, a forkhead family transcription factor specially expressed in regulatory T (Treg) cells, controls the expression of many key immune-regulatory genes. Treg cells are a population of T lymphocytes that have critical roles in the immune system homeostasis and tolerance to self and foreign antigens, the body's response to cancer and infectious agents. FOXP3 forms oligomeric complexes with other proteins, the components of which are believed to be regulated dynamically. In addition, HDAC activities influence FOXP3 interactions with other partners to form transcriptional regulatory complexes. By understanding the details of the biochemical and structural basis of the regulation of FOXP3 acetylation, therapeutic strategies for diseases related to Treg cells may emerge.

Figure 1

Structure of the HDAC7 catalytic domain. The crystal structure of the HDAC catalytic domain solved by Schuetz et al. (PDB code: 3c0y) is shown as a structural cartoon. Different secondary structures (alpha helix, beta strand and loop) are colored teal, magentas and salmon, respectively. The two coordinated zinc ions are colored grey.

Figure 2

Structure of the TIP60 acetyltransferase domain. The crystal structure of human TIP60 isoform 3 (PDB code: 2ou2) in a complex with acetyl coenzyme A is shown as a structural cartoon (Wu et al., to be published). Different secondary structures (alpha helix, beta strand and loop) are colored teal, magentas and salmon, respectively. Acetyl coenzyme A is shown as sticks and colored by atomic type (carbon: yellow; nitrogen: blue; oxygen: red; phosphorus: orange).

Figure 3

Structure of p300 HAT domain. Crystal structure of p300 HAT domain (PDB code: 3biy) was solved in complex with a bisubstrate inhibitor, Lys-CoA. Two HAT subdomains, amino acids 1287–1522 and amino acids 1569–1666, were co-purified and used for crystallization. The structure is showed as cartoon and colored by secondary structure (alpha helix: teal, beta strand: magentas; loop: salmon). The inhibitor in the structure is presented as sticks and colored by atomic type (carbon: yellow; nitrogen: blue; oxygen: red; phosphorus: orange).