NLRP1 encodes NACHT, LRR, FIIND, CARD domain and PYD domains-containing protein 1 in humans. NLRP1 was the first

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

shown to form an

inflammasome Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sens ...

. Material was copied from this source, which is available under
Creative Commons Attribution 4.0 International License
NLRP1 is expressed by a variety of

cell Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...

types, which are predominantly

epithelial Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

hematopoietic Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...

. The expression is also seen within glandular epithelial structures including the lining of the

small intestine The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...

stomach The stomach is a muscular, hollow organ in the upper gastrointestinal tract of Human, humans and many other animals, including several invertebrates. The Ancient Greek name for the stomach is ''gaster'' which is used as ''gastric'' in medical t ...

, airway epithelia and in hairless or glabrous skin. NLRP1 polymorphisms are associated with skin extra-intestinal manifestations in CD. Its highest expression was detected in human skin, in

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...

and in vitiligo. Polymorphisms of NLRP1 were found in

lupus erythematosus is a collection of autoimmune diseases in which the human immune system becomes hyperactive and attacks healthy tissues. Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, ...

and diabetes type 1. Variants of mouse NLRP1 were found to be activated upon N-terminal cleavage by the

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...

anthrax Anthrax is an infection caused by the bacterium '' Bacillus anthracis'' or ''Bacillus cereus'' biovar ''anthracis''. Infection typically occurs by contact with the skin, inhalation, or intestinal absorption. Symptom onset occurs between one ...

lethal factor.

Function

This gene encodes a member of the Ced-4 family of

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

proteins. Ced-family members contain a

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) and are known to be key mediators of

programmed cell death Programmed cell death (PCD) sometimes referred to as cell, or cellular suicide is the death of a cell (biology), cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usual ...

. The encoded

contains a distinct N-terminal pyrin-like motif, which is possibly involved in protein-protein interactions. The NLRP1 protein interacts strongly with

caspase 2 Caspase 2 also known as CASP2 is an enzyme that, in humans, is encoded by the ''CASP2'' gene. ''CASP2'' orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds ...

and weakly with

caspase 9 Caspase-9 is an enzyme that in humans is encoded by the ''CASP9'' gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, ...

. Overexpression of this

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 ...

was demonstrated to induce

pyroptosis Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of ...

in cells. Multiple

alternatively spliced Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

transcript variants encoding distinct isoforms have been found for this gene, but the biological validity of some variants has not been determined.

Mechanism of activation

NLRP1 activates an antibacterial or antiviral

immune response An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellula ...

. Antibacterial

compensates for the loss of the

MAP kinase A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammato ...

response. Humans produce NLRP1, but human NLRP1 is not activated by lethal factor. NLRP1 could be activated by proteolytic cleavage, resulting in the removal of an auto-inhibitory PYD and release of the CARD domain, responsible for the recruitment and activation of pro-caspase-1 in the active form of caspase-1. Human NLRP1 activation can be elicited by several means including enteroviral 3C proteases. Its function in

immunity Immunity may refer to: Medicine * Immunity (medical), resistance of an organism to infection or disease * ''Immunity'' (journal), a scientific journal published by Cell Press Biology * Immune system Engineering * Radiofrequence immunity ...

is just beginning to be understood.

Interactions

NLRP1 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...

with

and

APAF1 Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of ''C. elegans'' CED-4 gene. Function The protein was identified in the laboratory of Xiaodong Wang as an activator of caspase-3 in the presence of cytochromeC a ...

. Via its FIIND domain, NLRP1 interacts directly with

DPP9 Dipeptidyl peptidase 9 is an enzyme that in humans is encoded by the ''DPP9'' gene. Function This gene encodes a protein that is a member of the S9B family in clan SC of the serine proteases. The protein has been shown to have post-proline di ...

and

DPP8 Dipeptidyl peptidase 8 is an enzyme that in humans is encoded by the ''DPP8'' 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 tr ...

which are needed to prevent NLRP1 activation. Loss of DPP9 in humans and mice, results in NLRP1 activation.

Variants of NLRP1 in human

Several Mendelian diseases caused by NLRP1

germline mutation A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and Egg cell, ova). Mutations in these cells are the only mutations that can be passed on to offspring, when e ...

s have been described. These include Multiple Self-healing Palmoplantar Carcinoma, familial Nikam's disease and Autoinflammation with Arthritis and Dyskeratosis. Mutations in NLRP1, whether dominant or recessive, tend to be gain-of-function alleles that trigger

signaling with

IL1B 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" ...

and IL18 release.

Variants of NLRP1 in mice

Mice have three paralogs of the ''Nlrp1'' gene (''Nlrp1a, b, c''). ''Nlrp1c'' is a pseudogene. Mouse NLRP1B is not activated by a receptor-ligand type mechanism. NLRP1B variants from certain inbred mouse strains, BALB/c and 129, can be activated by the lethal factor (LF)

. The lethal factor

is produced and secreted by ''

Bacillus anthracis ''Bacillus anthracis'' is a gram-positive and rod-shaped bacterium that causes anthrax, a deadly disease to livestock and, occasionally, to humans. It is the only permanent (obligate) pathogen within the genus ''Bacillus''. Its infection is a ty ...

'', the agent of

. Together with protective antigen (PA), LF forms a bipartite toxin, Lethal Toxin. The role of PA is to form a translocation channel that delivers LF into the host cell

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

, where LF play roles in immune response by cleaving and inactivating MAP kinases. LF also directly cleaves NLRP1B proximal to its

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

, it is necessary and sufficient for NLRP1B

formation and CASP1 activation. Activation of NLRP1B-dependent

responses appears in host defense with mechanism like IL-1β and

neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...

s. NLRP1B can function as a sensor of

bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

s, immune responses are specifically activated by

virulence Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most cases, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its abili ...

factors. It is not clear what stimuli might activate NLRP1A, the other known functional murine NLRP1 paralog. The study identified a mouse carrying a missense gain-of-function

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

in NLRP1A (Q593P) that active

responses. The mechanism of

wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, " ...

NLRP1A activation is unclear.

References

External links

* {{NOD-like receptors LRR proteins NOD-like receptors