Biomedical Engineering Reference
In-Depth Information
presumably leading to increased levels of NIK. Accordingly, decreased TRAF3 levels
lead to constitutive p100 processing ([86] and personal observation). Notably,
TRAF2-deficient B cells also exhibit constitutive p100 processing, indicating a
similar role for TRAF2 [87]. Whether TRAF2-dependent activation of the alternative
NF-
B pathway also depends on NIK has not been published so far. Furthermore,
whether NIK activation itself requires other upstream kinases is unclear. Moderate
overexpression of NIK is sufficient for signaling, suggesting it is readily activated
by autophosphorylation. As such, it is possible that reduced degradation of NIK in
the absence of TRAF3 is sufficient to induce NIK activity, which leads to IKK
κ
α
activation and, together with NIK's property to support physical interaction of IKK
α
with p100, ultimately results in NF-
κ
B activation (
Figure 3.2b
).
3.4.2
A
CTIVATION
OF
THE
NF-
κ
B P
ATHWAY
BY
M
EMBERS
OF
THE
IL-1R/TLR F
AMILY
Members of the IL-1R family, such as IL-1R and IL-18R and members of the TLR
receptor family, such as TLR4, whose activation is triggered by lipopolysaccharide
(LPS), are also potent activators of the classic NF-
B pathway. Both IL-1R- and
TLR-family members share a common structural motif, the so-called TLR/IL-1R
(TIR) homology domain at their
cytoplasmic portion [88]. Comparable to TNFR
family members, TIR-containing receptors do not have catalytic activity, but recruit
intracellular adaptors and signal transducing molecules to activate various effector
pathways [89]. Homotypic TIR-TIR interactions between receptor domains and a
limited set of TIR-containing adaptors explain why more than 15 different receptors
trigger only a small number of signaling pathways [89].
Based on genetic evidence and limited biochemical analyses, two adaptor mol-
ecules, MyD88 and TRIF/TICAM1, define IL-1R/ TLR signaling. Some receptors,
like TLR3 or TLR9 seem to signal exclusively through either TRIF or MyD88,
respectively, while TLR4 uses both [89]. Most receptors in these groups, including
κ
IL-1R, IL18R, TLR1,2,5,6,7,8,9, seem to signal primarily through MyD88 (
Figure
κ
B activation also depends on a TRAF molecule, in
this case TRAF6, which is also involved in CD40 signaling [90,91]. MyD88-depen-
dent signaling also involves additional molecules that belong to the IRAK (IL-1R
associated kinase) family [88]. Two of the four IRAKs, IRAK1, and IRAK4 were
shown to be involved in IL-1R/TLR induced NF-
B activation [92-95]. Based on
data from knockout fibroblasts, both, IRAK1 and IRAK4 are required for IL-1
dependent NF-
κ
B (and JNK) activation
[93,95]. Interestingly, however, kinase activ-
ity is not required for IRAK1 and only partially required for IRAK4 signaling at
least in human cells [96,97]. The IRAKs are required to induce recruitment of
TRAF6 to MyD88, possibly through engagement of other molecules, such as TIFA
[98]. Although it cannot be excluded that IRAKs have functions other than TRAF6
recruitment, it is interesting to note that direct, IRAK-independent recruitment of
TRAF6 to CD40 or artificial dimerization/oligomerization of TRAF6 are sufficient
to initiate NF-
κ
B activation
[43,91]. Moreover, dimerization of MyD88, but not
TRAF6 leads to activation of IRAK1 [99], further supporting the notion that TRAF6
acts downstream of IRAK1/4, at least in respect to NF-
κ
κ
B activation.
