Inhibitor of nuclear factor kappa-B kinase subunit epsilon also known as I-kappa-B kinase epsilon or IKK-epsilon is an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''IKBKE''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Interactions
IKBKE has been shown to
interact with
TANK
A tank is an armoured fighting vehicle intended as a primary offensive weapon in front-line ground combat. Tank designs are a balance of heavy firepower, strong armour, and battlefield mobility provided by tracks and a powerful engine; ...
.
Function
It is a
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to viral infection, through the activation of the
type I IFN,
NF-kappa-B and
STAT signaling. Also involved in
TNFA and inflammatory
cytokine
Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling.
Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s, like
Interleukin-1
The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
Discovery
Discovery of these cytokines began with studies on t ...
, signaling. Following activation of
viral RNA sensors, such as
RIG-I-like receptors, associates with
DDX3X and
phosphorylates interferon regulatory factors (IRFs),
IRF3 and
IRF7, as well as DDX3X. This activity allows subsequent
homodimerization and nuclear translocation of the IRF3 leading to transcriptional activation of pro-inflammatory and antiviral genes including
IFNB. In order to establish such an antiviral state, IKBKE forms several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including
IPS1/MAVS,
TANK
A tank is an armoured fighting vehicle intended as a primary offensive weapon in front-line ground combat. Tank designs are a balance of heavy firepower, strong armour, and battlefield mobility provided by tracks and a powerful engine; ...
,
AZI2/NAP1 or TBKBP1/SINTBAD (TANK-binding kinase 1-binding protein 1) can be recruited to the IKBKE-containing-complexes. Activated by
polyubiquitination in response to TNFA and interleukin-1, regulates the NF-kappa-B signaling pathway through, at least, the phosphorylation of
CYLD. Phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. In addition, is also required for the induction of a subset of
ISGs which displays antiviral activity, may be through the phosphorylation of
STAT1 at 'Ser-708'. Phosphorylation of STAT1 at 'Ser-708' seems also to promote the assembly and DNA binding of
ISGF3 (STAT1:
STAT2:IRF9) complexes compared to GAF (gamma-activation factor) (STAT1:STAT1) complexes, in this way regulating the balance between
type I and
type II IFN responses. Protects cells against DNA damage-induced cell death. Also plays an important role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, which leads to a negative impact on
insulin sensitivity. Phosphorylates
AKT1
RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the ''AKT1'' gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) protein domains. It ...
.
Clinical significance
Inhibition of
IκB kinase (IKK) and IKK-related kinases, IKBKE (IKKε) and
TANK-binding kinase 1
TBK1 (TANK-binding kinase 1) is an enzyme with kinase activity. Specifically, it is a serine / threonine protein kinase. It is encoded by the TBK1 gene in humans. This kinase is mainly known for its role in innate immunity antiviral response. Ho ...
(TBK1), has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.
References
Further reading
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EC 2.7.11