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Impaired dendritic-cell function in ectodermal dysplasia with immune deficiency is linked to defective NEMO ubiquitination

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Impaired dendritic-cell function in ectodermal dysplasia with immune deficiency is linked to defective NEMO ubiquitination

Auteurs : Stephane T. Temmerman ; Chi A. Ma ; Louis Borges ; Marek Kubin ; Shuying Liu ; Jonathan M. J. Derry ; Ashish Jain

Source :

Blood [ 0006-4971 ] ; 2006.

RBID : PMC:1895566

Abstract

Ectodermal dysplasia with immune deficiency (EDI) is caused by alterations in NEMO (nuclear factor [NF]–κB essential modulator). Most genetic mutations are located in exon 10 and affect the C-terminal zinc finger domain. However, the biochemical mechanism by which they cause immune dysfunction remains undetermined. In this report, we investigated the effect of a cysteine-to-arginine mutation (C417R) found in the NEMO zinc finger domain on dendritic cell (DC) function. Following CD40 stimulation of DCs prepared from 2 unrelated patients with the NEMO C417R mutation, we found NEMO ubiquitination was absent, and this was associated with preserved RelA but absent c-Rel activity. As a consequence, CD40 stimulated EDI DCs failed to synthesize the c-Rel–dependent cytokine interleukin-12, had impaired up-regulation of costimulatory molecules, and failed to support allogeneic lymphocyte proliferation in vitro. In contrast, EDI DCs stimulated with the TLR4 ligand lipopolysaccharide (LPS) showed normal downstream NF-κB activity, DC maturation, and NEMO ubiquitination. These findings show for the first time how mutations in the zinc finger domain of NEMO can lead to pathway specific defects in NEMO ubiquitination and thus immune deficiency.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895566

DOI: 10.1182/blood-2006-04-017210
PubMed: 16794254
PubMed Central: 1895566

Affiliations:

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PMC:1895566

Le document en format XML

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<author><name sortKey="Temmerman, Stephane T" sort="Temmerman, Stephane T" uniqKey="Temmerman S" first="Stephane T." last="Temmerman">Stephane T. Temmerman</name>
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<author><name sortKey="Ma, Chi A" sort="Ma, Chi A" uniqKey="Ma C" first="Chi A." last="Ma">Chi A. Ma</name>
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<author><name sortKey="Borges, Louis" sort="Borges, Louis" uniqKey="Borges L" first="Louis" last="Borges">Louis Borges</name>
</author>
<author><name sortKey="Kubin, Marek" sort="Kubin, Marek" uniqKey="Kubin M" first="Marek" last="Kubin">Marek Kubin</name>
</author>
<author><name sortKey="Liu, Shuying" sort="Liu, Shuying" uniqKey="Liu S" first="Shuying" last="Liu">Shuying Liu</name>
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<author><name sortKey="Derry, Jonathan M J" sort="Derry, Jonathan M J" uniqKey="Derry J" first="Jonathan M. J." last="Derry">Jonathan M. J. Derry</name>
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<author><name sortKey="Jain, Ashish" sort="Jain, Ashish" uniqKey="Jain A" first="Ashish" last="Jain">Ashish Jain</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Impaired dendritic-cell function in ectodermal dysplasia with immune deficiency is linked to defective NEMO ubiquitination</title>
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<author><name sortKey="Ma, Chi A" sort="Ma, Chi A" uniqKey="Ma C" first="Chi A." last="Ma">Chi A. Ma</name>
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<author><name sortKey="Borges, Louis" sort="Borges, Louis" uniqKey="Borges L" first="Louis" last="Borges">Louis Borges</name>
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<author><name sortKey="Kubin, Marek" sort="Kubin, Marek" uniqKey="Kubin M" first="Marek" last="Kubin">Marek Kubin</name>
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<author><name sortKey="Liu, Shuying" sort="Liu, Shuying" uniqKey="Liu S" first="Shuying" last="Liu">Shuying Liu</name>
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<author><name sortKey="Derry, Jonathan M J" sort="Derry, Jonathan M J" uniqKey="Derry J" first="Jonathan M. J." last="Derry">Jonathan M. J. Derry</name>
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<author><name sortKey="Jain, Ashish" sort="Jain, Ashish" uniqKey="Jain A" first="Ashish" last="Jain">Ashish Jain</name>
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<series><title level="j">Blood</title>
<idno type="ISSN">0006-4971</idno>
<idno type="eISSN">1528-0020</idno>
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<front><div type="abstract" xml:lang="en"><p>Ectodermal dysplasia with immune deficiency (EDI) is caused by alterations in NEMO (nuclear factor [NF]–κB essential modulator). Most genetic mutations are located in exon 10 and affect the C-terminal zinc finger domain. However, the biochemical mechanism by which they cause immune dysfunction remains undetermined. In this report, we investigated the effect of a cysteine-to-arginine mutation (C417R) found in the NEMO zinc finger domain on dendritic cell (DC) function. Following CD40 stimulation of DCs prepared from 2 unrelated patients with the NEMO C417R mutation, we found NEMO ubiquitination was absent, and this was associated with preserved RelA but absent c-Rel activity. As a consequence, CD40 stimulated EDI DCs failed to synthesize the c-Rel–dependent cytokine interleukin-12, had impaired up-regulation of costimulatory molecules, and failed to support allogeneic lymphocyte proliferation in vitro<italic>.</italic>
 In contrast, EDI DCs stimulated with the TLR4 ligand lipopolysaccharide (LPS) showed normal downstream NF-κB activity, DC maturation, and NEMO ubiquitination. These findings show for the first time how mutations in the zinc finger domain of NEMO can lead to pathway specific defects in NEMO ubiquitination and thus immune deficiency.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
  <front><journal-meta><journal-id journal-id-type="nlm-ta">Blood</journal-id>
<journal-id journal-id-type="publisher-id">bloodjournal</journal-id>
<journal-title>Blood</journal-title>
<issn pub-type="ppub">0006-4971</issn>
<issn pub-type="epub">1528-0020</issn>
<publisher><publisher-name>The American Society of Hematology</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">16794254</article-id>
<article-id pub-id-type="pmc">1895566</article-id>
<article-id pub-id-type="publisher-id">2324</article-id>
<article-id pub-id-type="doi">10.1182/blood-2006-04-017210</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Immunobiology</subject>
</subj-group>
</article-categories>
<title-group><article-title>Impaired dendritic-cell function in ectodermal dysplasia with immune deficiency is linked to defective NEMO ubiquitination</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Temmerman</surname>
<given-names>Stephane T.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Ma</surname>
<given-names>Chi A.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Borges</surname>
<given-names>Louis</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Kubin</surname>
<given-names>Marek</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Shuying</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Derry</surname>
<given-names>Jonathan M. J.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Jain</surname>
<given-names>Ashish</given-names>
</name>
</contrib>
</contrib-group>
<aff id="N0x8d51ff8N0xa1461bc">From the Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD; and Amgen, Seattle, WA.</aff>
<author-notes><fn><p><bold>Reprints:</bold>
 Ashish Jain, CRC, Rm 5490, 10 Center Dr, National Institutes of Health, Bethesda, MD 20892; e-mail: <email>ajain@niaid.nih.gov</email>
. </p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>1</day>
<month>10</month>
<year>2006</year>
</pub-date>
<pub-date pub-type="epreprint"><day>22</day>
<month>6</month>
<year>2006</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>1</day>
<month>10</month>
<year>2007</year>
</pub-date>
<volume>108</volume>
<issue>7</issue>
<fpage>2324</fpage>
<lpage>2331</lpage>
<history><date date-type="received"><day>14</day>
<month>4</month>
<year>2006</year>
</date>
<date date-type="accepted"><day>30</day>
<month>5</month>
<year>2006</year>
</date>
</history>
<copyright-statement>Copyright © 2006, The American Society of Hematology</copyright-statement>
<copyright-year>2006</copyright-year>
<self-uri xlink:title="pdf" xlink:href="zh801906002324.pdf"></self-uri>
<abstract><p>Ectodermal dysplasia with immune deficiency (EDI) is caused by alterations in NEMO (nuclear factor [NF]–κB essential modulator). Most genetic mutations are located in exon 10 and affect the C-terminal zinc finger domain. However, the biochemical mechanism by which they cause immune dysfunction remains undetermined. In this report, we investigated the effect of a cysteine-to-arginine mutation (C417R) found in the NEMO zinc finger domain on dendritic cell (DC) function. Following CD40 stimulation of DCs prepared from 2 unrelated patients with the NEMO C417R mutation, we found NEMO ubiquitination was absent, and this was associated with preserved RelA but absent c-Rel activity. As a consequence, CD40 stimulated EDI DCs failed to synthesize the c-Rel–dependent cytokine interleukin-12, had impaired up-regulation of costimulatory molecules, and failed to support allogeneic lymphocyte proliferation in vitro<italic>.</italic>
 In contrast, EDI DCs stimulated with the TLR4 ligand lipopolysaccharide (LPS) showed normal downstream NF-κB activity, DC maturation, and NEMO ubiquitination. These findings show for the first time how mutations in the zinc finger domain of NEMO can lead to pathway specific defects in NEMO ubiquitination and thus immune deficiency.</p>
</abstract>
</article-meta>
<notes><fn-group><fn><p>Prepublished online as <italic>Blood</italic>
 First Edition Paper, June 22, 2006; DOI 10.1182/blood-2006-04-017210.</p>
</fn>
<fn><p>An Inside <italic>Blood</italic>
 analysis of this article appears at the front of this issue.</p>
</fn>
<fn><p>The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.</p>
</fn>
</fn-group>
</notes>
</front>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey="Borges, Louis" sort="Borges, Louis" uniqKey="Borges L" first="Louis" last="Borges">Louis Borges</name>
<name sortKey="Derry, Jonathan M J" sort="Derry, Jonathan M J" uniqKey="Derry J" first="Jonathan M. J." last="Derry">Jonathan M. J. Derry</name>
<name sortKey="Jain, Ashish" sort="Jain, Ashish" uniqKey="Jain A" first="Ashish" last="Jain">Ashish Jain</name>
<name sortKey="Kubin, Marek" sort="Kubin, Marek" uniqKey="Kubin M" first="Marek" last="Kubin">Marek Kubin</name>
<name sortKey="Liu, Shuying" sort="Liu, Shuying" uniqKey="Liu S" first="Shuying" last="Liu">Shuying Liu</name>
<name sortKey="Ma, Chi A" sort="Ma, Chi A" uniqKey="Ma C" first="Chi A." last="Ma">Chi A. Ma</name>
<name sortKey="Temmerman, Stephane T" sort="Temmerman, Stephane T" uniqKey="Temmerman S" first="Stephane T." last="Temmerman">Stephane T. Temmerman</name>
</noCountry>
</tree>
</affiliations>
</record>

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Impaired dendritic-cell function in ectodermal dysplasia with immune deficiency is linked to defective NEMO ubiquitination

Impaired dendritic-cell function in ectodermal dysplasia with immune deficiency is linked to defective NEMO ubiquitination

Source :

Abstract

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Le document en format XML

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