Biomedical Engineering Reference
In-Depth Information
PCAF
p300/CBP
Ac
Ac
Ac
Ac
Ac
K122/123
K218 K221
K310
1
550
p65
TA
Reduced
Binding to
κB Enhancer
Reduced
Transcriptional
Activity
Increased
κB Enhancer
Binding
Reduced
IκBα
Binding
Increased
Transcriptional
Activity
FIGURE 5.2
Acetylation of lysines by the p300/CBP and PCAF acetyltranferases regulates
distinct functions of p65. Five primary sites of p65 acetylation have been identified: lysines
122, 123, 218, 221, and 310. Acetylation of lysine 221 by p300/CBP enhances the DNA
binding affinity of p65 for the
κ
B-enhancer and together with acetylation of lysine 218 sharply
impairs the binding of I
κ
B
α
to p65. In contrast, acetylation of lysine 310 does not modulate
either DNA binding or I
assembly, but instead leads to enhanced transcriptional activity.
It is not clear whether acetylated lysine 310 serves as a platform for binding of a transcriptional
coactivator. Conversely, acetylation of lysines 122 and 123 by both p300 and p300/CBP-
PCAF reduces the binding of p65 to the
κ
B
α
B enhancer and impairs the overall transcriptional
activity of p65. These findings emphasize how the acetylation of different lysine residues in
p65 can shape its action in very specific and different ways.
κ
p300/CBP- and PCAF-mediated acetylation of p65 may occur in a cell-type-specific
manner, leading to very different transcriptional outcomes [71,72].
The biological importance of the reversible acetylation of p65 is highlighted by
its role in regulating the assembly of p65 with its specific inhibitor, I
κ
B
α
[52].
Stimulus-coupled activation of NF-
κ
B is associated with the near-complete depletion
of I
κ
B
α
. However, among many target genes, NF-
κ
B upregulates expression of the
I
α
proteins can shuttle in and out the nucleus and participate in the retrieval of nuclear
NF-
κ
B
α
gene, leading to resynthesis of this inhibitor [73]. Newly synthesized I
κ
B
κ
B, a response that terminates the NF-
κ
B-mediated transcriptional response
(
Figure 5.3
)
[74,75]. This retrieval function of I
κ
B
α
is regulated by the acetylation
status of p65. Specifically, when p65 is acetylated at lysines 218 and 221, it cannot
bind effectively to I
. However, deacetylation of p65 at these sites by HDAC3
greatly enhances its binding to I
κ
B
α
and leads, in turn, to a rapid chromosomal
region maintenance (CRM
)
1-dependent nuclear export of the NF-
κ
B
α
B complex [52].
This export response marks the end of the transcriptional response and helps to
replenish the depleted cytoplasmic pool of latent NF-
κ
κ
B/I
κ
B
α
complexes, thereby
readying the cell for the next NF-
B-inducing stimulus. As such, the reversible
acetylation of p65 serves as an intranuclear molecular switch that shapes both the
strength and duration of the NF-
κ
B response [52]. In support of this model, treatment
of human leukemia cells with HDAC inhibitors like superoylanilide hydroxamic acid
(SAHA) or MS-275 markedly increases the levels of acetylated p65, enhances the
nuclear accumulation of p65, and diminishes the association of p65 with I
κ
κ
B
α
[76].
