title: Two lysines in the forkhead domain of foxp3 are key to T regulatory cell function.
abstract: BACKGROUND
  The forkhead box transcription factor, Foxp3, is master regulator of the development and function of CD4+CD25+ T regulatory (Treg) cells that limit autoimmunity and maintain immune homeostasis. The carboxyl-terminal forkhead (FKH) domain is required for the nuclear localization and DNA binding of Foxp3. We assessed how individual FKH lysines contribute to the functions of Foxp3 in Treg cells.
  
  
  RESULTS
  We found that mutation of FKH lysines at position 382 (K17) and at position 393 (K18) impaired Foxp3 DNA binding and inhibited Treg suppressive function in vivo and in vitro. These lysine mutations did not affect the level of expression of Foxp3 but inhibited IL-2 promoter remodeling and had important and differing effects on Treg-associated gene expression.
  
  
  CONCLUSIONS
  These data point to complex effects of post-translational modifications at individual lysines within the Foxp3 FKH domain that affect Treg function. Modulation of these events using small molecule inhibitors may allow regulation of Foxp3+ Treg function clinically.
authors.affiliation: Laboratory of Medicine, Division of Transplant Immunology, Department of Pathology, School of Medicine, University of Pennsylvania, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Liu
authors.forename: Liqing
authors.initials: L
authors.lastname: Wang
authors.forename: Rongxiang
authors.initials: R
authors.lastname: Han
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Beier
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018800:Thy-1 Antigens / Q000502:physiology
chemical_list: D015415:Biomarkers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D007376:Interleukin-2; D012333:RNA, Messenger; D018800:Thy-1 Antigens; C064658:RAG-1 protein; D004247:DNA; D008239:Lysine