Biomedical Engineering Reference
In-Depth Information
component, nuclear factor
κ
B essential modifier (NEMO)/IKK
γ
, has subsequently
been identified through genetic complementation of an NF-
B activation-defective
cell line [1] and sequencing of IKK-associated polypeptides [2,3]. Although NEMO
does not have catalytic properties, cell lines defective for NEMO do not activate
NF-
κ
B in response to many stimuli, which demonstrates the key role of this protein
in activating the NF-
κ
B pathway. The human
nemo
gene is located on chromosome
X at Xq28
[4] and encodes a 45 kD protein composed of several structural domains,
among them two coiled-coil domains, a leucine zipper, and a C-terminal zinc finger.
It is required for IKK activation in response to most NF-
κ
B stimuli (classical or
canonical pathway), as shown using mutant cell lines defective for this protein. In
contrast, a subset of stimuli, including B cell activating factor (BAFF) and lympho-
toxin-
κ
), does not require NEMO, but instead induces IKK activation through
nuclear factor
β
(LT
β
κ
B inducing kinase (NIK)-induced IKK
α
phosphorylation (alternative
or noncanonical pathway) [5,6].
The exact mechanism of IKK activation and the identity of the molecules that
regulate its activity remain poorly understood (
Chapter 3
). Very recently, it has been
proposed that IKK activation by cytokines and lipopolysaccharide (LPS) may involve
nondegradative ubiquitination events [7], a modification that might be negatively con-
trolled by the cylindromatosis (CYLD) deubiquitinase (see
Section 9.5
and
Chapter 4
).
9.2
INCONTINENTIA PIGMENTI AND NEMO
LOSS-OF-FUNCTION MUTATIONS
The story starts with a consortium of geneticists looking for the gene whose mutation
is responsible for an X-linked neurocutaneous genodermatosis called Incontinentia
pigmenti (IP) [8]. In males, IP is lethal during early development. In females, the
most characteristic feature of the disease is a dermatosis that usually begins after
birth and evolves according to the following sequence: (1) an erythematous, vascular
rash develops, accompanied by a massive eosinophilic granulocyte infiltration into
the epidermis; (2) verrucous hyperkeratotic lesions evolve and disappear over time,
leaving behind areas of hyperpigmentation; and (3) this hyperpigmentation fades
and pale hairless patches or streaks remain on the skin.
In addition to these epidermal manifestations, IP patients also suffer from oph-
talmologic (abnormalities of the developing retinal vessels), odontological (missing
or deformed teeth) and, in rare cases, neurological (convulsive disorders, motor or
mental retardation) problems. An important characteristic of IP is the skewed X-inac-
tivation that occurs in several cell types or tissues of female patients. This skewing
reflects a counter-selection of cells carrying the mutated copy of NEMO and can
reach, in blood cells for instance, more than 95%.
The gene responsible for IP was localized to Xq28, similar to NEMO. This
localization, as well as the high sensitivity to apoptosis of IP cells, suggested that
it might be responsible for the observed pathology
.
Indeed, the analysis of a large
number of patients showed that 85% of them carried the same complex rearrange-
ment of the NEMO
gene [9], resulting in the excision of the region between two
repeated sequences located upstream of exon 4 and downstream of exon 10. The
first three exons of NEMO, those
that remain after the rearrangement, produce a
