Biology Reference
In-Depth Information
epithelial cells of the intestine, lung, and oral cavity
[79]
. Both NOD1
and NOD2 are primarily located in the cytosol and both sense bacterial
molecules produced during the synthesis, degradation, and remodeling
of PGN, a major component of bacterial cell walls
[79]
. PGN is a poly-
mer composed of glycan chains of alternating
N
-acylglucosamine and
N
-acetylmuramic acid units cross-linked to each other by short peptides.
NOD2 senses muramyl dipeptide (MDP), which is found in the PGN of
nearly all gram-positive and gram-negative organisms, whereas NOD1
recognizes
meso
-diaminopimelic acid (
meso
-DAP)-containing PGN frag-
ments, which are unique to PGN from most gram-negative bacteria and
certain gram-positive bacteria (the dipeptide γ-D-glutamyl-
meso
-DAP is
the core motif that is sufficient to trigger NOD1)
[83,84]
. Following micro-
bial sensing, NOD1 or NOD2 directly recruit the serine-threonine kinase
RIP-like interacting CLARP kinase (also known as receptor-interacting
protein 2) through CARD-CARD interactions resulting in the activation
of NF-κB and MAPKs
[79]
. NOD1 and NOD2 are involved in the sens-
ing of numerous pathogenic bacteria. NOD1 detects the gram-negative
Shigella,
enteroinvasive
Escherichia coli, Chlamydia, Pseudomonas,
Campylobacter,
and
Helicobacter.
Pathogens that activate NOD2 include
Streptococcus pneumoniae, Mycobacterium tuberculosis, Salmonella
typhimurium, Listeria,
and
Yersinia
[79,85,86]
. In addition to sensing
bacterial moieties, NOD1 and NOD2 have been implicated in modulat-
ing the adaptive immune response
[79]
.
434
There is strong evidence that deregulation of NOD1 and NOD2 signal-
ing causes or contributes to a variety of human diseases. Genetic stud-
ies revealed that several NOD2 variants are associated with susceptibility
to Crohn's disease (CD)
[87,88]
. Although multiple variants of NOD2
have been found be linked to CD, three of them (R702W, G908R, and
L1007insC), involving amino acid residues near or within the LRRs of
NOD2, are relatively common
[87,88]
. Individuals homozygous or com-
pound heterozygous for the common NOD2 mutations have about
20-fold increased risk for disease development, whereas heterozygous
subjects have only about 2-fold increased risk
[87,88]
. Biochemical and
functional studies revealed that the human CD-associated NOD2 vari-
ants exhibit reduced or loss of ability to activate NF-κB in response to
MDP, but they maintain a normal response to lipopolysaccharide stim-
ulation
[89]
. By contrast, missense mutations resulting in single amino
acid substitutions within the NOD of NOD2 cause Blau syndrome
[90]
.
In contrast to CD, the NOD2 mutations associated with these diseases
exhibit constitutive NF-κB activation and enhanced response to MDP
[91]
. NOD1 polymorphisms have been identified that are associated with
increased risk of developing asthma as well as with increased levels of
serum IgE in several human populations, but the mechanisms by which
NOD1 variants increase the susceptibility to these allergic diseases is
unknown
[92]
.
INFLAMMASOMES
NLRPs, namely, NLRP1, NLRP3, and NLRC4, and the cytosolic receptor
AIM2 are the four types of inflammasomes that link microbial and endog-
enous danger signals to the activation of caspase 1
[77,80,82]
.
Search WWH ::
Custom Search