NLRP1

Official Full Name

NLR family pyrin domain containing 1

Organism

Homo sapiens

GeneID

22861

Background

This gene encodes a member of the Ced-4 family of apoptosis proteins. Ced-family members contain a caspase recruitment domain (CARD) and are known to be key mediators of programmed cell death. The encoded protein contains a distinct N-terminal pyrin-like motif, which is possibly involved in protein-protein interactions. This protein interacts strongly with caspase 2 and weakly with caspase 9. Overexpression of this gene was demonstrated to induce apoptosis in cells. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

Synonyms

NAC; JRRP; MSPC; AIADK; CARD7; CIDED; NALP1; SLEV1; DEFCAP; PP1044; VAMAS1; CLR17.1; DEFCAP-L/S;

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Detailed Information

The NLRP1 gene is 96 Kb in length and contains 49 exons. Its encoded protein is a member of the NLR family of nucleotide oligomeric domain-like receptors and contains a set of cytoplasmic pattern recognition receptors, which are rich in leucine repeats (LRR) and are capable of non-specific recognition of microbial surface molecules, thereby activating innate immunity. The NLRP1 signaling pathway is mainly composed of the receptor NLRP1, the adaptor protein ASC and the effector protein caspase-1.

NLRP1 Figure 1. Mechanisms of NLRP1-Mediated Autoinflammatory Disease in Humans and Mice. (Yu, C. H., et al. 2017)

Biological Function of NLRP1

The main activating substances of NLRP1 inflammasome have been found to include: muramyl dipeptide (MDP), anthrax lethal toxin (LT), and parasites such as Toxoplasma gondii, which are found in almost all bacteria. NLRP1 is widely present in T cells, B cells, monocytes, macrophages, dendritic cells, and granulocytes. NLRP1 inflammasome promotes the maturation of IL-1β, IL-18 and IL-33, and plays an important role in the inflammatory response and anti-infection of human body. IL-1β promotes inflammatory responses such as leukocyte infiltration, lymphocyte activation, acute phase protein induction, and fever. It binds to the IL-1β receptor and induces the secretion of a large number of inflammatory and chemokines.

There is an inhibitory regulation of the NLRP1 inflammasome in the normal body, so that the activation of the inflammasome is in a strict regulation. The currently known negative regulation pathways of NLRP1 inflammasome are as follows: (1) Self-inhibition: The NACHT domain interacts with the LRR domain to inhibit self-activation. (2) Proteins containing a CARD domain: For example, a single CARD protein, an inhibitory CARD protein, Caspase-12, etc. interfere with the assembly of Caspase-1 in an inflammatory body. (3) Proteins containing a PYD domain: for example, heat shock proteins interfere with the interaction of ASC with NLRP1. (4) Anti-apoptotic proteins: For example, Bcl-2 and Bcl-XL interact with the NACHT-LRR domain of NLRP1 to inhibit the activation of Caspase-1. (5) Viral proteins: For example, Kaposi's sarcoma virus, herpes virus and the like can bind to NLRP1 and other NLR family proteins to inhibit the activation of inflammatory bodies.

NLRP1 Inflammatory Body and Disease

By detecting the mRNA levels of TNF-α and monocytes in patients, it was found that the NLRP1 inflammasome mRNA content changed significantly in the early stage of infection, and the change of this content was positively correlated with the survival of patients: surviving infected patients The amount of NLRP1 expressed was higher than that of the deceased. Anthrax is caused by the invasion of Bacillus anthracis. The release of LT from Bacillus anthracis can induce an NLRP1-dependent immune response in mice, enhance lysosomal membrane permeability, release cytoplasmic cathepsin, and mediate cell pyroptosis. In the process of Toxoplasma infection, NLRP1 inflammasome affects the susceptibility and immune response of congenital toxoplasmosis in humans. RNA interference with NLRP1 expression results in a dull immune response to Toxoplasma infection by monocytes, which accelerates the death and lysis of infected cells. All of this indicates that NLRP1 is an important component of the innate immune response and plays an important role in the clearance of pathogenic bacteria. On the other hand, the study found that LT can activate the macrophage NLRP1 inflammatory body and Caspase-1, which cause LT-sensitive macrophage lysis and animal death after B. anthracis infection. This illustrates the complexity of the role of NLRP1 inflammasome in immune infections.

References:

Yu, C. H. , Moecking, J. , Geyer, M. , & Masters, S. L. . (2017). Mechanisms of nlrp1-mediated autoinflammatory disease in humans and mice. Journal of Molecular Biology, 430(2).
Relja, B., Horstmann, J. P., Kontradowitz, K., Jurida, K., Schaible, A., & Neunaber, C., et al. (2015). Nlrp1 inflammasome is downregulated in trauma patients. Journal of Molecular Medicine, 93(12), 1391-1400.
Lacey, C. A. , & Miao, E. A. . (2019). Nlrp1 - one nlr to guard them all. The EMBO journal.

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