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.
