Class of proteins
Structure and domain organization of
NOD2
, a human NOD-like receptor
The
nucleotide-binding oligomerization domain-like receptors
, or
NOD-like receptors
(
NLRs
) (also known as nucleotide-binding leucine-rich repeat receptors),
[1]
are intracellular sensors of
pathogen-associated molecular patterns (PAMPs)
that enter the cell via
phagocytosis
or pores, and
damage-associated molecular patterns (DAMPs)
that are associated with cell stress. They are types of
pattern recognition receptors (PRRs)
,
[2]
and play key roles in the regulation of
innate immune response
. NLRs can cooperate with
toll-like receptors (TLRs)
and regulate inflammatory and
apoptotic
response.
NLRs primarily recognize
Gram-positive bacteria
, whereas TLRs primarily recognize
Gram-negative bacteria
. They are found in
lymphocytes
,
macrophages
,
dendritic cells
and also in non-immune cells, for example in
epithelium
.
[3]
NLRs are highly conserved through evolution. Their homologs have been discovered in many different animal species (
APAF1
)
[4]
[5]
and also in the plant kingdom (
disease-resistance R protein
).
[5]
Structure
[
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]
NLRs contain 3 domains ? central
NACHT
(NOD or NBD ? nucleotide-binding domain) domain, which is common to all NLRs, most of NLRs have also C-terminal
leucine-rich repeat
(LRR) and variable N-terminal interaction domain. NACHT domain mediates ATP-dependent self-oligomerization and LRR senses the presence of ligand. N-terminal domain is responsible for homotypic protein-protein interaction and it can consist of
caspase recruitment domain
(CARD),
pyrin domain
(PYD), acidic transactivating domain or
baculovirus inhibitor repeats
(BIRs).
[3]
[6]
Nomenclature and system
[
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Names as CATERPILLER, NOD, NALP, PAN, NACHT, PYPAF were used to describe the NLRs family. The nomenclature was unified by the
HUGO Gene Nomenclature Committee
in 2008. The family was characterized as NLRs to provide description of the families features ? NLR means nucleotide-binding domain and leucine-rich repeat containing gene family.
[7]
This system divides NLRs into 4 subfamilies based on the type of N-terminal domain:
- NLRA (A for acidic transactivating domain):
CIITA
- NLRB (B for
BIRs
):
NAIP
- NLRC (C for
CARD
):
NOD1
,
NOD2
,
NLRC3
,
NLRC4
,
NLRC5
- NLRP (P for
PYD
):
NLRP1
,
NLRP2
,
NLRP3
,
NLRP4
,
NLRP5
,
NLRP6
,
NLRP7
,
NLRP8
,
NLRP9
,
NLRP10
,
NLRP11
,
NLRP12
,
NLRP13
,
NLRP14
[7]
There is also an additional subfamily NLRX which doesn't have significant homology to any N-terminal domain. A member of this subfamily is
NLRX1
.
[8]
On the other hand, NLRs can be divided into 3 subfamilies with regard to their phylogenetic relationships:
- NODs:
NOD1
,
NOD2
,
NOD3
(
NLRC3
),
NOD4
(
NLRC5
),
NOD5
(
NLRX1
),
CIITA
- NLRPs (also called NALPs):
NLRP1
,
NLRP2
,
NLRP3
,
NLRP4
,
NLRP5
,
NLRP6
,
NLRP7
,
NLRP8
,
NLRP9
,
NLRP10
,
NLRP11
,
NLRP12
,
NLRP13
,
NLRP14
- IPAF:
IPAF
(
NLRC4
),
NAIP
[9]
Subfamily NODs
[
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]
NODs subfamily consists of NOD1, NOD2, NOD3, NOD4 with CARD domain, CIITA containing acidic transactivator domain and NOD5 without any N-terminal domain.
[9]
[10]
Signalling
[
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The well-described receptors are NOD1 and NOD2. The recognition of their ligands recruits oligomerization of NACHT domain and CARD-CARD interaction with CARD-containing serine-threonin
kinase RIP2
which leads to activation of RIP2.
[11]
RIP2 mediates the recruitment of kinase TAK1 which phosphorylates and activates
IκB kinase
. The activation of IκB kinase results in the phosphorylation of inhibitor IκB which releases
NF-κB
and its nuclear translocation. NF-κB then activates expression of
inflammatory cytokines
.
[12]
Mutations in NOD2 are associated with
Crohn's disease
[13]
or
Blau syndrome
.
[14]
Ligands
[
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]
NOD1 and NOD2 recognize
peptidoglycan
motifs from bacterial cell which consists of
N-acetylglucosamine
and
N-acetylmuramic acid
. These sugar chains are cross-linked by peptide chains that can be sensed by NODs. NOD1 recognizes a molecule called
meso-diaminopimelic acid
(meso-DAP) mostly found in
Gram-negative bacteria
(for example
Helicobacter pylori
,
Pseudomonas aeruginosa
). NOD2 proteins can sense intracellular
muramyl dipeptide
(MDP), typical for bacteria such as
Streptococcus pneumoniae
or
Mycobacterium tuberculosis
.
[3]
[10]
Subfamilies NLRPs and IPAF
[
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]
NLRPs subfamily contains NLRP1-NLRP14 that are characterized by the presence of PYD domain. IPAF subfamily has two members ? IPAF with CARD domain and NAIP with BIR domain.
[9]
[10]
Signalization
[
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]
NLRPs and IPAF subfamilies are involved in the formation of the
inflammasome
. The best characterized inflammasome is
NLRP3
, the activation through
PAMPs
or
DAMPs
leads to the oligomerization.
[9]
The pyrin domain of NLRs binds to an adaptor protein
ASC (PYCARD)
via PYD-PYD interaction. ASC contains PYD and CARD domain and links the NLRs to inactive form of
caspase 1
through the CARD domain.
[15]
All these protein-protein interaction form a complex called the inflammasome. The aggregation of the pro-caspase-1 causes the autocleavage and formation of an active enzyme. Caspase-1 is important for the proteolytic processing of the pro-inflammatory cytokines
IL-1β
and
IL-18
.
[9]
[10]
NLRP3 mutations are responsible for the autoinflammatory disease
familial cold autoinflammatory syndrome
or
Muckle?Wells syndrome
.
[16]
[17]
Ligands
[
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]
There are three well-characterized inflammasomes ? NLRP1, NLRP3 and IPAF. The formation of
NLRP3 inflammasome
can be activated by
PAMPs
such as microbial toxins (for example alpha-toxin of
Staphylococcus aureus
) or whole pathogens, for instance
Candida albicans
,
Saccharomyces cerevisiae
,
Sendai virus
,
Influenza
. NLRP3 recognize also
DAMPs
which indicate stress in the cell. The danger molecule can be extracellular ATP, extracellular glucose,
monosodium urate (MSU) crystals
, calcium pyrophosphate dihydrate (CPPD),
alum
,
cholesterol
or environmental irritants ?
silica
,
asbestos
,
UV
irradiation and skin irritants. The presence of these molecules causes a production of
ROS
and K+ efflux. NLRP1 recognizes lethal toxin from
Bacillus anthracis
and
muramyl dipeptide
. IPAF senses
flagellin
from
Salmonella typhimurium
,
Pseudomonas aeruginosa
,
Listeria monocytogenes
.
[3]
[9]
[10]
See also
[
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]
References
[
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]
- ^
Mahla, Ranjeet (2013).
"Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology"
.
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- ^
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.
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.
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.
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.
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External links
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]