Biomedical Engineering Reference
In-Depth Information
mutant lacking a conserved cysteine within the protease domain, blocks the activa-
tion of IKK and MAP kinases [164].
4.7.2
U
BIQUITIN
-M
EDIATED
P
ROTEOLYSIS
OF
U
PSTREAM
R
EGULATORY
P
ROTEINS
B activation has been shown to be controlled
by proteolysis of specific upstream signaling proteins, in addition to RIP. This
involves the addition of ubiquitin to target proteins by specific E3s.
One mechanism to shut off receptor activation of NF-
In several examples the duration of NF-
κ
B is the proteolysis of
activating receptors. The C-terminus of TNFRII interacts with the ankyrin repeat
and SOCS box (ASB) family member, ASB3 [165]. ASB3 recruits the E3 adaptors
Elongins-B/C to TNFRII, leading to ubiquitination of the cytoplasmic tail on mul-
tiple lysines, which triggers TNFRII proteolysis by the proteasome. Downregulation
of ASB3 by RNA interference blocks TNFRII degradation induced by TNF
κ
stim-
ulation and potentiates TNFRII-mediated cytotoxicity. In an analogous fashion,
Triad3A, a RING finger E3, interacts with the cytoplasmic tail of TLR9 and induces
TLR9 ubiquitination and proteolytic degradation [166]. Knockdown of Triad3A by
RNA interference blocks CpG-induced degradation of TLR9 and enhances activation
of NF-
α
B by CpG.
Following stimulation of TNFRII, TRAF2 is ubiquitinated (presumably with
K48-linked ubiquitin) and its levels decrease due to proteasome-mediated proteolysis
[167]. Degradation of TRAF2 has been suggested to be triggered by cIAP-1 (cellular
inhibitor of apoptosis 1) based on the inhibitory effects of cIAP-1 RING mutants
on TRAF2 ubiquitination and proteolysis [167]. cIAP-1 can recruit E2 ubiquitin-
conjugating enzymes via its RING domain and function as an E3 [168]. Recent
experiments have indicated that ubiquitination of TRAF2 by c-IAP-1 involves their
colocation with the ER-associated E2 Ubc6 in a perinuclear compartment [169].
cIAP-1 and cIAP-2 have also been reported to interact with RIP, triggering its
ubiquitination [170]. Genetic support for these functions of IAPs is currently lacking,
but it is possible that these proteins, whose expression is regulated by NF-
κ
B [171],
are part of a negative feedback loop to terminate receptor activation of NF-
κ
κ
B by
triggering proteolysis of specific intracellular signaling proteins.
Downregulation of NF-
B activation by the TCR involves the TCR-induced
ubiquitination and degradation of BCL-10 [172]. Overexpression experiments sug-
gest that the HECT domain ubiquitin ligases NEDD4 and Itch promote BCL-10
ubiquitination. The possible role of Itch in BCL10 degradation is particularly inter-
esting since Itch-deficient mice display an activated phenotype that is consistent
with stabilization of BCL-10 [173]. In anergic T cells, NEDD4 and Itch have also
been implicated in triggering the ubiquitination and proteolysis of PLC
κ
γ
1 (phos-
B by the
TCR [174]. The type of ubiquitin linkage attached to BCL-10 has not been deter-
mined; however, degradation of PLC
pholipase C
γ
1) and PKC
θ
, which are both essential for activation of NF-
κ
and BCL-10 is not mediated by the
proteasome and, at least for BCL-10, involves transient localization to lysosomal
vesicles [172,174]. It is, therefore, possible that BCL-10 is not ubiquitinated by
K48-linked ubiquitin.
γ
1, PKC
θ,
