NLRP

NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of NOD-like receptor.[1] NLRP proteins are part of the innate immunity and detect conserved pathogen characteristics such as peptidoglycan. It is thought that NLRP proteins sense inherent danger, and link this with microbial products, creating a response under the concept of the inflammasome including K+ efflux and caspase 1 activation.[2] NLRP is also known to be associated with a number of hereditary diseases. Research suggests NLRP proteins may be involved in combating retroviruses in gametes.[3] Currently there are at least 13 known human NALP genes named as NALP1 through NALP13.[3]

Function

NLRP plays a key role in inflammation and fevers. It is a scaffolding protein and is crucial for aggregating other proteins that form the inflammasome. It activates caspase-1 and assists in the maturation of the proinflammatory cytokines IL-1β and IL-18. As with other NOD-like receptors, NLRP functions to recognize danger signals. NALP3 for instance has been observed to play a significant role propagating immune response to aluminum in adjuvants.[3][4][5][6]

Structure

NLRP protein structure has a N-terminal PYD domain followed by NACHT domain and several leucine-rich repeats (LRR). These PYD domains can interact with other PYD domains to allow for interaction between NRLP and other proteins also containing a PYD domain.[3][4][7]

Expression

NLRP1 is highly expressed in neutrophils, monocytes, dendritic cells, B and T cells. NLRP was found in high density in T-cell region of the spleen, but not found in B cell regions. Both the brain and the testis expressed NLRP1 but not NLRP3. NLRP1 was found in the neurons of the brain.[4]

NALP gene

In humans, NRLP genes are found on the following chromosomal localizations: 17p13, 19q13.42, 1q44, 19q13.43, 11p15.5, and 11p15.4. Most NRLP genes are found on chromosome 19 and 11, however, the most abundant NLRPs (NLRP1 and NLRP3) are found on 17p13 and 1q44. NLRP has been frequently observed to undergo gene duplication events.[3][4]

Associated hereditary diseases

Mutations in the NLRP3 is responsible for a number of hereditary diseases: MWS (Muckle-Wells Syndrome), FCAS (Familial Cold Autoinflammatory Syndrome) and CINCA (Chronic Infantile Neurological Cutaneous Articular syndrome). All of which involve periodic fever, joint inflammation, rashes and amyloidosis. Mutations in NLRP genes that cause hereditary diseases is much more common than that of other PAMP receptors for unknown reasons. Experiments have suggested that Muckle-Wells syndrome is closely tied to IL-1 signaling, as when IL-1 receptor antagonists are introduced to patients, their inflammatory symptoms are no longer observed.[3][4][7]

Role in plants

In plants, danger signal sensors have been identified to contain many NALPs and therefore it is proposed that NALPs can also serve as danger signal sensors.[3]

Genes

Some NLRP genes code for a series of NACHT, LRR and PYD domains-containing proteins, including:

  • NLRP1, a human gene that encodes the NACHT, LRR and PYD domains-containing protein 1
  • NLRP2, a human gene that encodes the NACHT, LRR and PYD domains-containing protein 2
  • NLRP3, a human gene that encodes the NACHT, LRR and PYD domains-containing protein 3
  • NLRP4, a human gene that encodes the NACHT, LRR and PYD domains-containing protein 4
  • NLRP7, a human gene that encodes the NACHT, LRR and PYD domains-containing protein 7
  • NLRP12, a human gene that encodes the NACHT, LRR and PYD domains-containing protein 12

Some NLRP genes encode a series of NOD-like receptor family pyrin domains, including:

  • NLRP5, a human gene that encodes the NOD-like receptor family pyrin domain containing 5
  • NLRP6, a human gene that encodes the NOD-like receptor family pyrin domain containing 6
  • NLRP8, a human gene that encodes the NOD-like receptor family pyrin domain containing 8
  • NLRP9, a human gene that encodes the NOD-like receptor family pyrin domain containing 9
  • NLRP10, a human gene that encodes the NOD-like receptor family pyrin domain containing 10
  • NLRP11, a human gene that encodes the NOD-like receptor family pyrin domain containing 11
  • NLRP13, a human gene that encodes the NOD-like receptor family pyrin domain containing 13
  • NLRP14, a human gene that encodes the NOD-like receptor family pyrin domain containing 14

References
  1. So, A (2008). "Developments in the scientific and clinical understanding of gout". Arthritis Research & Therapy. 10 (5): 221. doi:10.1186/ar2509. PMC 2592794. PMID 18947374.
  2. Martinon, F; Mayor, A; Tschopp, J (2009). "The inflammasomes: guardians of the body". Annu. Rev. Immunol. 27: 229–265. doi:10.1146/annurev.immunol.021908.132715. PMID 19302040.
  3. Martinon, Fabio; Gaide, Olivier; Pétrilli, Virgine; Mayor, Annick; Tschopp, Jürg (2007-09-01). "NALP Inflammasomes: a central role in innate immunity". Seminars in Immunopathology. 29 (3): 213–29. doi:10.1007/s00281-007-0079-y. ISSN 1863-2297. PMID 17703304.
  4. Kummer, J. Alain; Broekhuizen, Roel; Everett, Helen; Agostini, Laetitia; Kuijk, Loes; Martinon, Fabio; Bruggen, Robin van; Tschopp, Jürg (22 January 2007). "Inflammasome Components NALP 1 and 3 Show Distinct but Separate Expression Profiles in Human Tissues Suggesting a Site-specific Role in the Inflammatory Response". Journal of Histochemistry & Cytochemistry. 55 (5): 443–452. doi:10.1369/jhc.6a7101.2006. PMID 17164409.
  5. Kolliputi, Narasaiah; Galam, Lakshmi; Tamarapu Parthasarathy, Prasanna; Tipparaju, Srinivas M.; Lockey, Richard F. (2012-09-01). "NALP-3 inflammasome silencing attenuates ceramide-induced transepithelial permeability". Journal of Cellular Physiology. 227 (9): 3310–3316. doi:10.1002/jcp.24026. ISSN 1097-4652. PMC 3323724. PMID 22169929.
  6. Kolly, Laeticia; Karababa, Mahir; Joosten, Leo A. B.; Narayan, Sharmal; Salvi, Roberto; Pétrilli, Virginie; Tschopp, Jurg; Berg, Wim B. van den; So, Alexander Kai-Lik (2009-09-15). "Inflammatory Role of ASC in Antigen-Induced Arthritis Is Independent of Caspase-1, NALP-3, and IPAF". The Journal of Immunology. 183 (6): 4003–4012. doi:10.4049/jimmunol.0802173. ISSN 0022-1767. PMID 19717512.
  7. Dinarello, Charles A. (2004-03-01). "Unraveling the NALP-3/IL-1β Inflammasome: A Big Lesson from a Small Mutation". Immunity. 20 (3): 243–244. doi:10.1016/S1074-7613(04)00055-X. ISSN 1074-7613. PMID 15030767.
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