FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease.
We have found that FOXP3 is an oligomeric component of a large supramolecular complex. Certain FOXP3 mutants with single amino acid deletions in the leucine zipper domain of FOXP3 are associated with the X-linked autoimmunity-allergic dysregulation (XLAAD) and immunodysregulation, polyendocrinopathy and enteropathy, X-linked (IPEX) syndrome in humans. We report that the single amino acid deletion found in human XLAAD/IPEX patients within the leucine zipper domain of FOXP3 does not disrupt its ability to join the larger protein complex, but eliminates FOXP3 homo-oligomerization as well as heteromerization with FOXP1. We found that the zinc finger-leucine zipper domain region of FOXP3 is sufficient to mediate both homodimerization and homotetramerization. However, the same domain region from XLAAD/IPEX FOXP3 containing an E251 deletion prevents oligomerizaton and the protein remains monomeric. We also found that wild-type FOXP3 directly binds to the human IL-2 promoter, but the E251 deletion in FOXP3 in XLAAD/IPEX patient's T cells disrupts its association with the IL-2 promoter in vivo and in vitro, and limits repression of IL-2 transcription after T-cell activation. Our results suggest that compromising FOXP3 homo-oligomerization and hetero-oligomerization with the FOXP1 protein impairs DNA-binding properties leading to distinct biochemical phenotypes in humans with the XLAAD/IPEX autoimmune syndrome. This study explains some features of the pathogenesis of a disease syndrome that arises as a consequence of specific assembly failure of a transcriptional repressor due to certain mutations within the FOXP3 leucine zipper.
Li
Bin
B
Department of Pathology and Laboratory Medicine, University of Pennsylvania, 252 John Morgan Building, 36th and Hamilton Walk, Philadelphia, PA 19104-6082, USA.
Samanta
Arabinda
A
Song
Xiaomin
X
Iacono
Kathryn T
KT
Brennan
Patrick
P
Chatila
Talal A
TA
Roncador
Giovanna
G
Banham
Alison H
AH
Riley
James L
JL
Wang
Qiang
Q
Shen
Yuan
Y
Saouaf
Sandra J
SJ
Greene
Mark I
MI
D002460:Cell Line; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic
C486626:FOXP1 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D046912:Multiprotein Complexes; D012097:Repressor Proteins