NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3
ALP3and cryopyrin), is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''NLRP3''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
located on the long arm of
chromosome 1
Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ar ...
.
NLRP3 is expressed predominantly in
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s and as a component of the
inflammasome
Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-in ...
,
detects products of damaged cells such as extracellular
ATP and crystalline
uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of ...
. Activated NLRP3 in turn triggers an immune response. Mutations in the NLRP3 gene are associated with a number of organ specific
autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s.
Nomenclature
NACHT, LRR, and PYD are respectively acronyms for:
*
NACHT –
NAIP (neuronal apoptosis
inhibitor protein
The inhibitor protein (IP) is situated in the mitochondrial matrix and protects the cell against rapid ATP hydrolysis during momentary ischaemia
Ischemia American and British English spelling differences#ae and oe, or ischaemia is a restric ...
),
C2TA
MHC,_
HET-E_(Podospora_anserina#Heterokaryon_incompatibility.html" ;"title="Major_histocompatibility_complex.html" ;"title="lass 2 transcription activator, of the
MHC,_
HET-E_(Podospora_anserina#Heterokaryon_incompatibility">heterokaryon_incompatibility)_and_
TP1_(telomerase-associated_protein_1)
*_
MHC,_
HET-E_(Podospora_anserina#Heterokaryon_incompatibility">heterokaryon_incompatibility)_and_
TP1_(telomerase-associated_protein_1)
*_Leucine-rich_repeat">LRR_–_"
leucine-
rich_
repeat"__and_is_synonymous_with_NLR,_for_''_or_''
nucleotide-binding_domain,_
leucine-rich_
repeat"
*_Pyrin_domain.html" ;"title="Leucine-rich_repeat.html" ;"title="Major histocompatibility complex">MHC, HET-E (Podospora anserina#Heterokaryon incompatibility">heterokaryon incompatibility) and TP1 (telomerase-associated protein 1)
* Leucine-rich repeat">LRR – "leucine-rich repeat" and is synonymous with NLR, for '' or ''nucleotide-binding domain, leucine-rich repeat"
* Pyrin domain">PYD – "PYRIN domain," after the ''pyrin'' proteins The ''NLRP3'' gene name abbreviates "NLR family, pyrin domain containing 3," where NLR refers to "nucleotide-binding domain, leucine-rich repeat."
The NACHT, LRR and PYD domains-containing protein 3 is also called:
* cold induced autoinflammatory syndrome 1 (CIAS1),
* caterpiller-like receptor 1.1 (CLR1.1), and
* PYRIN-containing APAF1-like protein 1 (PYPAF1).
Structure
This gene encodes a pyrin-like protein which contains a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with pyrin domain (PYD) of apoptosis-associated speck-like protein containing a CARD (ASC). Proteins which contain the caspase recruitment domain
Caspase recruitment domains, or caspase activation and recruitment domains (CARDs), are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate th ...
, CARD, have been shown to be involved in inflammation and immune response.
Function
NLRP3 is a component of the innate immune system
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
that functions as a pattern recognition receptor
Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...
(PRR) that recognizes pathogen-associated molecular pattern
Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. A vast arra ...
s (PAMPs). NLRP3 belongs to the NOD-like receptor
The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs) (also known as nucleotide-binding leucine-rich repeat receptors), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the ...
(NLR) subfamily of PRRs and NLRP3 together with the adaptor ASC protein PYCARD
PYCARD, often referred to as ASC (Apoptosis-associated speck-like protein containing a CARD), is a protein that in humans is encoded by the ''PYCARD'' gene. It is localized mainly in the nucleus of monocytes and macrophages. In case of pathogen in ...
forms a caspase-1
Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolysis, proteolytically cleaves other proteins, such as the Protein precursor, precursors of the inflammatory cytokines Interleukin 1 beta, interleuki ...
activating complex known as the NLRP3 inflammasome
Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-in ...
. NLRP3 in the absence of activating signal is kept in an inactive state complexed with HSP90
Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...
and SGT1 in the cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
. NLRP3 inflammasome detects danger signals such as crystalline uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of ...
and extracellular ATP released by damaged cells. These signals release HSP90 and SGT1 from and recruit ASC protein and caspase-1 to the inflammasome complex. Caspase-1 within the activated NLRP3 inflammasome complex in turn activates the inflammatory cytokine, IL-1β
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
.
The NLRP3 inflammasome appears to be activated by changes in intracellular potassium caused by potassium efflux from mechanosensitive ion channel Mechanosensitive channels, mechanosensitive ion channels or stretch-gated ion channels
(not to be confused with mechanoreceptors). They are present in the membranes of organisms from the three domains of life: bacteria, archaea, and eukarya. They ...
s located in the cell membrane. It appears that NLRP3 is also regulated by reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(ROS), though the precise mechanisms of such regulation has not been determined.
It is suggested that NLRP3 provides protection against ''Streptococcus pneumoniae
''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They are ...
'' infections by activating STAT6
Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor com ...
and SPDEF
SAM pointed domain-containing Ets transcription factor is a protein that in humans is encoded by the ''SPDEF'' gene.
PDEF is an ETS transcription factor expressed in prostate epithelial cells. It acts as an androgen-independent transactivator of P ...
.
Pathology
Mutations in the NLRP3 gene have been associated with a spectrum of dominantly inherited autoinflammatory disease
Periodic fever syndromes are a set of disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by abnormalities of ...
s called cryopyrin-associated periodic syndrome
Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by Interleukin 1 beta, interleukin 1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervo ...
(CAPS). This includes familial cold autoinflammatory syndrome
Cold urticaria (essentially meaning cold hives) is a disorder in large red welts called hives (''urticaria'') form on the skin after exposure to a cold stimulus. The hives are usually itchy and often the hands and feet will become itchy and swoll ...
(FCAS), Muckle–Wells syndrome
Muckle–Wells syndrome (MWS) is a rare autosomal dominant disease which causes sensorineural deafness and recurrent hives, and can lead to amyloidosis. Individuals with MWS often have episodic fever, chills, and joint pain. As a result, MWS is ...
(MWS), chronic infantile neurological cutaneous and articular (CINCA
Neonatal-onset multisystem inflammatory disease is a rare genetic periodic fever syndrome which causes uncontrolled inflammation in multiple parts of the body starting in the newborn period. Symptoms include skin rashes, severe arthritis, and chr ...
) syndrome, neonatal onset multisystem inflammatory disease (NOMID), and keratoendotheliitis fugax hereditaria
Keratoendotheliitis fugax hereditaria is an autosomal dominantly inherited disease of the cornea, caused by a point mutation in cryopyrin (also known as NALP3) that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome ...
.
Defects in this gene have also been linked to familial Mediterranean fever
Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in Mediterranean fever gene, which encodes a 781–amino acid protein called pyrin. While all ethnic groups are sus ...
. In addition, the NLRP3 inflammasome has a role in the pathogenesis
Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...
of gout
Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intensit ...
, hemorrhagic stroke and neuroinflammation
Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury,Ebert SE, Jensen P, Ozenne B, Armand S, Svarer C, Stenbaek DS ''et al.'' Molecular imaging of ...
occurring in protein-misfolding diseases, such as Alzheimer's
Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...
, Parkinson's
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, and prion disease
Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It i ...
s. Amelioration of mouse models of many diseases has been shown to occur by deletion of the NLRP3 inflammasome, including gout
Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intensit ...
, type 2 diabetes
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
, multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
, Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, and atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
. The compound β-Hydroxybutyrate
β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid or BHB, is an organic compound and a beta hydroxy acid with the chemical formula CH3CH(OH)CH2CO2H; its conjugate base is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxyb ...
has been shown to block NLRP3 activation, and thus may be of benefit for many of these diseases.
Deregulation of NLRP3 has been connected with carcinogenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
. For example, all the components of the NLRP3 inflammasome are downregulated or completely lost in human hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
It occurs in t ...
.
Inhibition
The NLRP3 inflammasome has garnered attention as a potential drug target for a variety of diseases underpinned by inflammation. The diarylsulfonylurea MCC-950 has been identified as a potent and selective NLRP3 inhibitor.[ ] Nodthera and Inflazome, have entered phase I clinical trials with NLRP3 inhibitors. Another NLRP3 antagonist is Dapansutrile
Dapansutrile (OLT1177) is an inhibitor of the NLRP3 (nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3) inflammasome.
An inflammasome can be defined as an immune system Receptor (biochemistry), receptor that indu ...
(OLT1177). This β-sulfonyl nitrile molecule compound was developed by Olactec Therapeutics, and is a selective NLRP3 inhibitor. Dapansutrile, been used in clinical trials as a remedy for heart failure, osteoarthritis and gouty arthritis.
References and notes
External links
*
{{DEFAULTSORT:Nalp3
LRR proteins
Human proteins
NOD-like receptors