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Blood, 1 October 2006, Vol. 108, No. 7, pp. 2324-2331. Prepublished online as a Blood First Edition Paper on June 22, 2006; DOI 10.1182/blood-2006-04-017210. This Article Full Text (PDF) All Versions of this Article: blood-2006-04-017210v1 108/7/2324    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Temmerman, S. Articles by Jain, A. Search for Related Content PubMed PubMed Citation Articles by Temmerman, S. Articles by Jain, A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 14, 2006 Accepted May 30, 2006 Impaired dendritic cell function in ectodermal dysplasia with immune deficiency is linked to defective NEMO ubiquitination Stephane Temmerman, Chi A. MA, Louis Borges, Marek Kubin, Shuying Liu, Jonathan Derry, and Ashish Jain* Laboratory of Host Defenses, National Institute of Allergy, and Infectious Diseases, NIH Amgen Inc, Seattle, Washington * Corresponding author; email: ajain{at}niaid.nih.gov. Ectodermal dysplasia with immune deficiency (EDI) is caused by alterations in NEMO (NF-B essential modulator). The majority of 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 function. Following CD40 stimulation of DCs prepared from two 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 fail to synthesize the c-Rel dependant cytokine interleukin 12, have impaired upregulation of co-stimulatory molecules, and fail to support allogeneic lymphocyte proliferation in vitro. In contrast, EDI DCs stimulated with the TLR4 ligand lipopolysaccharide (LPS) showed normal downstream NF-B 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: That fish (NEMO) again? Gulbu Uzel Blood 2006 108: 2135. [Full Text] [PDF] This article has been cited by other articles: A. Singh, K. A. Zarember, D. B. Kuhns, and J. I. Gallin Impaired Priming and Activation of the Neutrophil NADPH Oxidase in Patients with IRAK4 or NEMO Deficiency J. Immunol., May 15, 2009; 182(10): 6410 - 6417. [Abstract] [Full Text] [PDF] F. Cordier, O. Grubisha, F. Traincard, M. Veron, M. Delepierre, and F. Agou The Zinc Finger of NEMO Is a Functional Ubiquitin-binding Domain J. Biol. Chem., January 30, 2009; 284(5): 2902 - 2907. [Abstract] [Full Text] [PDF]

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