Biomedical Engineering Reference
In-Depth Information
point mutations, scattered all along the molecule, lead to EDA-ID, and while they
sometimes affect the C-terminal zinc finger
(such as the C417R mutation described
above, which probably interferes with Zn coordination), their effect on the structure
of NEMO remains difficult to predict in most cases. Clearly, a crystal structure of
the NEMO/IKK complex is needed before one can gain further understanding of
these pathologies.
9.4
I
MUTATION IS ASSOCIATED WITH EDA AND
T CELL IMMUNODEFICIENCY
κ
B
α
B cascade lead to symptoms similar
to those described above? Two recently described patients may help to answer this
question but may, at the same time, point toward the complexity of this signaling
pathway [41,42]. These patients exhibit an autosomal-dominant form of EDA-ID
but show no mutation in the NEMO gene. The developmental, immunological,
and infectious defects exhibited by these patients and by those carrying hypomor-
phic NEMO mutations largely overlap and include EDA, impaired cellular
responses to ligands of Toll-like receptors (TLR) and tumor necrosis factor receptor
(TNFR) superfamily members, and severe bacterial diseases. However, these new
patients exhibit a unique T cell immunodeficiency; despite a marked blood lym-
phocytosis, no detectable memory T cells can be seen
in vivo,
and naïve T cells
do not respond to CD3-TCR activation
ex vivo
. These patients have been demon-
strated to carry a heterozygous missense mutation at serine 32 of I
Do mutations in other components of the NF-
κ
This
residue, together with Ser36, is a target for IKK and is required to induce I
κ
B
α.
α
polyubiquitination and degradation. This mutation is a gain-of-function, as it
enhances the inhibitory capacity of I
κ
B
κ
B
α
by preventing its degradation and results
in impaired NF-
B activation. Currently, it is difficult to understand why these
patients show this unique T cell defect. It must be concluded that partially inhib-
iting the degradation of the 3 I
κ
B inhibitors (in the case of the hypomorphic
NEMO mutations) and completely inhibiting the degradation of the most important
of them, I
κ
, leads to different outcomes (although the magnitude of the differ-
ence might vary depending on the cell type considered). These results highlight
both the diversity of genotypes associated with EDA-ID and the diversity of
immunological phenotypes associated with mutations in different components of
the NF-
κ
B
α
κ
B signaling pathway.
9.5
CYLD DEUBIQUITINASE NEGATIVELY REGULATES
NF-
κ
B SIGNALING
In view of the importance of NEMO in human pathologies, interaction partners have
been sought by numerous groups. Recently, three groups used different approaches
to clone a cDNA, encoding a protein called CYLD, a member of a specific subclass
of deubiquitinases [43-45]. CYLD had been shown to be a tumor suppressor,
mutated in a pathology called cylindromatosis [46]. Familial cylindromatosis/Spie-
gler-Brooke syndrome (OMIM#132700) is a rare autosomal dominant inherited
