AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome

Massimiliano Gaetani, Vittoria Matafora, Mario Saare, Dimitrios Spiliotopoulos, Luca Mollica, Giacomo Quilici, Francesca Chignola, Mannella Valeria Mannella, Chiara Zucchelli, Pärt Peterson, Angela Bachi, Giovanna Musco

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Mutations in autoimmune regulator (AIRE) gene cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. AIRE is expressed in thymic medullary epithelial cells, where it promotes the expression of peripheral-tissue antigens to mediate deletional tolerance, thereby preventing selfreactivity. AIRE contains two plant homeodomains (PHDs) which are sites of pathological mutations. AIRE-PHD fingers are important for AIRE transcriptional activity and presumably play a crucial role in the formation of multimeric protein complexes at chromatin level which ultimately control immunological tolerance. As a step forward the understanding of AIRE-PHD fingers in normal and pathological conditions, we investigated their structure and used a proteomic SILAC approach to assess the impact of patient mutations targeting AIRE-PHD fingers. Importantly, both AIRE-PHD fingers are structurally independent and mutually noninteracting domains. In contrast to D297A and V301M on AIRE-PHD1, the C446G mutation on AIRE-PHD2 destroys the structural fold, thus causing aberrant AIRE localization and reduction of AIRE target genes activation. Moreover, mutations targeting AIRE-PHD1 affect the formation of a multimeric protein complex at chromatin level. Overall our results reveal the importance of AIREPHD domains in the interaction with chromatinassociated nuclear partners and gene regulation confirming the role of PHD fingers as versatile protein interaction hubs for multiple binding events.

Original languageEnglish
Pages (from-to)11756-11768
Number of pages13
JournalNucleic Acids Research
Volume40
Issue number22
DOIs
Publication statusPublished - Dec 2012

Fingerprint

Fingers
Chromatin
Mutation
Regulator Genes
Autoimmune Polyendocrinopathies
Proteins
Proteomics
Transcriptional Activation
Epithelial Cells
Antigens
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Gaetani, M., Matafora, V., Saare, M., Spiliotopoulos, D., Mollica, L., Quilici, G., ... Musco, G. (2012). AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome. Nucleic Acids Research, 40(22), 11756-11768. https://doi.org/10.1093/nar/gks933

AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome. / Gaetani, Massimiliano; Matafora, Vittoria; Saare, Mario; Spiliotopoulos, Dimitrios; Mollica, Luca; Quilici, Giacomo; Chignola, Francesca; Valeria Mannella, Mannella; Zucchelli, Chiara; Peterson, Pärt; Bachi, Angela; Musco, Giovanna.

In: Nucleic Acids Research, Vol. 40, No. 22, 12.2012, p. 11756-11768.

Research output: Contribution to journalArticle

Gaetani, M, Matafora, V, Saare, M, Spiliotopoulos, D, Mollica, L, Quilici, G, Chignola, F, Valeria Mannella, M, Zucchelli, C, Peterson, P, Bachi, A & Musco, G 2012, 'AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome', Nucleic Acids Research, vol. 40, no. 22, pp. 11756-11768. https://doi.org/10.1093/nar/gks933
Gaetani M, Matafora V, Saare M, Spiliotopoulos D, Mollica L, Quilici G et al. AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome. Nucleic Acids Research. 2012 Dec;40(22):11756-11768. https://doi.org/10.1093/nar/gks933
Gaetani, Massimiliano ; Matafora, Vittoria ; Saare, Mario ; Spiliotopoulos, Dimitrios ; Mollica, Luca ; Quilici, Giacomo ; Chignola, Francesca ; Valeria Mannella, Mannella ; Zucchelli, Chiara ; Peterson, Pärt ; Bachi, Angela ; Musco, Giovanna. / AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome. In: Nucleic Acids Research. 2012 ; Vol. 40, No. 22. pp. 11756-11768.
@article{fc017c4a811b43bd8134e28a526a2ed2,
title = "AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome",
abstract = "Mutations in autoimmune regulator (AIRE) gene cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. AIRE is expressed in thymic medullary epithelial cells, where it promotes the expression of peripheral-tissue antigens to mediate deletional tolerance, thereby preventing selfreactivity. AIRE contains two plant homeodomains (PHDs) which are sites of pathological mutations. AIRE-PHD fingers are important for AIRE transcriptional activity and presumably play a crucial role in the formation of multimeric protein complexes at chromatin level which ultimately control immunological tolerance. As a step forward the understanding of AIRE-PHD fingers in normal and pathological conditions, we investigated their structure and used a proteomic SILAC approach to assess the impact of patient mutations targeting AIRE-PHD fingers. Importantly, both AIRE-PHD fingers are structurally independent and mutually noninteracting domains. In contrast to D297A and V301M on AIRE-PHD1, the C446G mutation on AIRE-PHD2 destroys the structural fold, thus causing aberrant AIRE localization and reduction of AIRE target genes activation. Moreover, mutations targeting AIRE-PHD1 affect the formation of a multimeric protein complex at chromatin level. Overall our results reveal the importance of AIREPHD domains in the interaction with chromatinassociated nuclear partners and gene regulation confirming the role of PHD fingers as versatile protein interaction hubs for multiple binding events.",
author = "Massimiliano Gaetani and Vittoria Matafora and Mario Saare and Dimitrios Spiliotopoulos and Luca Mollica and Giacomo Quilici and Francesca Chignola and {Valeria Mannella}, Mannella and Chiara Zucchelli and P{\"a}rt Peterson and Angela Bachi and Giovanna Musco",
year = "2012",
month = "12",
doi = "10.1093/nar/gks933",
language = "English",
volume = "40",
pages = "11756--11768",
journal = "Nucleic Acids Research",
issn = "0305-1048",
publisher = ". This work is written by (a) US Government employee(s) and is in the public domain in the US",
number = "22",

}

TY - JOUR

T1 - AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome

AU - Gaetani, Massimiliano

AU - Matafora, Vittoria

AU - Saare, Mario

AU - Spiliotopoulos, Dimitrios

AU - Mollica, Luca

AU - Quilici, Giacomo

AU - Chignola, Francesca

AU - Valeria Mannella, Mannella

AU - Zucchelli, Chiara

AU - Peterson, Pärt

AU - Bachi, Angela

AU - Musco, Giovanna

PY - 2012/12

Y1 - 2012/12

N2 - Mutations in autoimmune regulator (AIRE) gene cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. AIRE is expressed in thymic medullary epithelial cells, where it promotes the expression of peripheral-tissue antigens to mediate deletional tolerance, thereby preventing selfreactivity. AIRE contains two plant homeodomains (PHDs) which are sites of pathological mutations. AIRE-PHD fingers are important for AIRE transcriptional activity and presumably play a crucial role in the formation of multimeric protein complexes at chromatin level which ultimately control immunological tolerance. As a step forward the understanding of AIRE-PHD fingers in normal and pathological conditions, we investigated their structure and used a proteomic SILAC approach to assess the impact of patient mutations targeting AIRE-PHD fingers. Importantly, both AIRE-PHD fingers are structurally independent and mutually noninteracting domains. In contrast to D297A and V301M on AIRE-PHD1, the C446G mutation on AIRE-PHD2 destroys the structural fold, thus causing aberrant AIRE localization and reduction of AIRE target genes activation. Moreover, mutations targeting AIRE-PHD1 affect the formation of a multimeric protein complex at chromatin level. Overall our results reveal the importance of AIREPHD domains in the interaction with chromatinassociated nuclear partners and gene regulation confirming the role of PHD fingers as versatile protein interaction hubs for multiple binding events.

AB - Mutations in autoimmune regulator (AIRE) gene cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. AIRE is expressed in thymic medullary epithelial cells, where it promotes the expression of peripheral-tissue antigens to mediate deletional tolerance, thereby preventing selfreactivity. AIRE contains two plant homeodomains (PHDs) which are sites of pathological mutations. AIRE-PHD fingers are important for AIRE transcriptional activity and presumably play a crucial role in the formation of multimeric protein complexes at chromatin level which ultimately control immunological tolerance. As a step forward the understanding of AIRE-PHD fingers in normal and pathological conditions, we investigated their structure and used a proteomic SILAC approach to assess the impact of patient mutations targeting AIRE-PHD fingers. Importantly, both AIRE-PHD fingers are structurally independent and mutually noninteracting domains. In contrast to D297A and V301M on AIRE-PHD1, the C446G mutation on AIRE-PHD2 destroys the structural fold, thus causing aberrant AIRE localization and reduction of AIRE target genes activation. Moreover, mutations targeting AIRE-PHD1 affect the formation of a multimeric protein complex at chromatin level. Overall our results reveal the importance of AIREPHD domains in the interaction with chromatinassociated nuclear partners and gene regulation confirming the role of PHD fingers as versatile protein interaction hubs for multiple binding events.

UR - http://www.scopus.com/inward/record.url?scp=84871186320&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84871186320&partnerID=8YFLogxK

U2 - 10.1093/nar/gks933

DO - 10.1093/nar/gks933

M3 - Article

C2 - 23074189

AN - SCOPUS:84871186320

VL - 40

SP - 11756

EP - 11768

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 22

ER -