Biomedical Engineering Reference
In-Depth Information
NEMO sumoylation is required for its nuclear translocation and IKK activation in
response to DSB, but not LPS-induced NF-
B activation. The authors also noticed
DSB-dependent ubiquitination of NEMO, which was ATM-dependent and followed
its sumoylation, most likely involving replacement of NEMO-attached SUMO with
polyubiquitin chains. Based on these experiments it has been proposed that SUMO-
dependent nuclear translocation juxtaposes NEMO and ATM, which, when activated
by DSBs phosphorylate NEMO, triggering its ubiquitination and nuclear export,
ultimately resulting in binding of modified NEMO to IKK
κ
α/β
and IKK activation
(
Figure 3.5
).
Certainly, many aspects of this model need to be further confirmed and
characterized. The ATM-phosphorylation sites in NEMO, the nuclear export mech-
anism, and whether ubiquitination of NEMO is required for direct activation of IKK
or nuclear export remain to be discovered.
Interestingly, DSB-mediated NF-
B activation also depends directly on RIP1
[124]. Moreover, cell treatment with adriamycin induced interaction of RIP1 with
NEMO, which was dependent on ATM, implying that RIP1 acts downstream of
ATM. Comparable to TNF
κ
α
, kinase activity of RIP1 was found to be dispensable
for DSB-mediated NF-
B activation. Based on these observations and the above
described modifications of NEMO, it is tempting to speculate that NEMO ubiquit-
ination controls interaction of NEMO with RIP1, which might serve as a scaffold
protein, possibly leading to oligomerization and activation of IKK (Figure 3.5).
Certainly, several aspects of this model are speculation and the exact mode of RIP1
and NEMO interaction and their relation to the active large IKK complex containing
IKK
κ
and NEMO need to be investigated. Nevertheless, this example of an
apparently different mechanism of IKK activation may also shed light on other
pathways regulating NF-
α/β
κ
B activity.
3.5
SUMMARY
Since IKK was cloned in 1997, substantial progress has been made in understanding
activation of IKK and NF-
B. It is now clear that IKK activation is the critical step
in all major pathways leading to NF-
κ
B activation. Many new molecules that are
involved in different pathways leading to IKK activation have been identified and
their biological roles have been confirmed in gene deficient mice or even human
κ
disease (
Chapter 9
). Identification of new molecules in these pathways and charac-
terization of their biological function has further substantiated the overall signifi-
cance of NF-
B in physiological and pathophysiological conditions, including
immune responses, inflammation, and cancer. Yet, despite the undeniable increase
in knowledge about IKK activation, the exact molecular mechanism and interactions
between IKK and upstream and downstream molecules is still surprisingly unclear.
Therefore, it is currently not possible to say whether all major molecules involved
in IKK activation have been described and just need to be assembled in the correct
way, or, whether we still are missing critical molecules, whose identification is
required to allow us to put the pieces of the puzzle together. The characterization
of the biochemical events leading to IKK activation is still a major challenge and
yet, it will probably be the understanding of the molecular details involved that will
allow us to influence this pathway in human disease.
κ
