Biomedical Engineering Reference
In-Depth Information
TNF
α
LPS
Ag / MHC
TNF-R I
TCR
TLR-4
Ub
Ub
Ub
Ub
Ub
Ub
Ub
Ub
TRADD
TRAF2
Ub
Ub
Ub
Ub
Itch/
NEDD4
A20
cIAP
TRAF6
Ub
Ub
Ub
Ub
TRAF6
CYLD
TAB2/3
A20
CYLD
Ub
Ub
Ub
Ub
NEMO
IKKα/β
CYLD
ELKS
P
P
p50
p65
SCF
βTrCP
Ub
Ub
P
IκBα
Proteasome
Cytoplasm
SOCS-1
P
Ac
Nucleus
p65
p50
N
F-κB B.
S
.
B signaling pathways. This schematic diagram high-
lights the role of ubiquitination in activation of the canonical NF-
FIGURE 4.2
Receptor-induced NF-
κ
B signaling pathway by
different receptor types. Ubiquitination is involved in two steps of the NF-
κ
B activation
process. transforming growth factor-beta-activated kinase 1 (TAK1) mitogen associated pro-
tein 3 (MAP 3)-kinase is activated by recruitment via TAB2/3 to K63-linked polyubiquitinated
proteins, such as TRAF2/6 and NF-
κ
B essential modifier (NEMO), and then subsequently
activates the IKK complex. IKK phosphorylation of I
κ
triggers its K48-linked polyubiq-
uitination and proteasome-mediated degradation, releasing associated p50/p65 heterodimers
to translocate into the nucleus and activate gene transcription. Cylindromatosis (CYLD) and
A20 both negatively regulate NF-
κ
B
α
B by removing K63-linked polyubiquitin from target
proteins. A20 additionally functions as an E3 ligase, which catalyzes the addition of K48-
linked polyubiquitin chains to RIP, triggering its proteasome-mediated degradation. Itch and
NEDD4 E3 ligases polyubiquitinate BCL-10, inducing its proteolysis, possibly in lyzosomes.
IKKa phosphorylates p65 triggering its polyubiquitination and proteasome-mediated degra-
dation. Suppressor of cytokine signaling 1 (SOCS1) is thought to function as an E3 ligase
for p65. I
κ
κ
B
α
is shown as a prototypical NF-
κ
B regulated gene. I
κ
B
α
forms a negative
feedback loop to shut off NF-
B activation by removing p50/p65 dimers from DNA and
transporting them back to the cytoplasm. Polyubiquitinated (Ub) and phosphorylated (P)
proteins are indicated. Abbreviations are defined in the text.
κ
