NLRP6

Official Full Name

NLR family pyrin domain containing 6

Organism

Homo sapiens

GeneID

171389

Background

The protein encoded by this gene binds arginine-vasopressin and may be involved in the arginine-vasopressin-mediated regulation of renal salt-water balance. The encoded protein also mediates inflammatory responses in the colon to allow recovery from intestinal epithelial damage and protects against tumorigenesis and the development of colitis. Finally, this protein can increase activation of NF-kappa-B, activation of CASP1 through interaction with ASC, and cAMP accumulation. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2013]

Synonyms

AVR; NAVR; PAN3; NALP6; PYPAF5; CLR11.4; NAVR/AVR;

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Detailed Information

NLRP6 is one of the NLRs family subclass NLRP, the coding gene is located on human chromosome 11, the N-terminus is the pyrin domain (PYD), and the middle is the nucleotide coupling domain (NACHT/NOD). The C-terminus is a leucine-rich repeat (LRR). Unlike other NLRs family proteins, NLRP6 is the first NLR protein family member to be found to suppress the signaling pathways involved in the innate immune response, which inhibits the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways. NLRP6 can form an intracellular polyprotein complex with Caspase-1 and a CARD-like protein-containing CARD (ASC) via a protein-protein linkage of the N-terminal PYD domain. It is called the NLRP6 inflammatory complex and belongs to a kind of inflammasomes, which is involved in the immune response of the inflammatory response.

NLRP6 Figure 1. Function of NLRP6, NLRP10, and NLRP12 in intestinal homeostasis and dendritic cell (DC) homing. (Ratsimandresy, R. A., et al. 2013)

Biological Function of NLRP6 Protein

NLRP6 is most expressed in neutrophils and T lymphocytes, followed by macrophages, epithelial cells, and dendritic cells. NLRP6 can be expressed in epithelial cells of various organs such as bladder, kidney, liver, lung, duodenum, ileum, cecum and colon. It is also abundantly present in human peripheral blood mononuclear cells (PBMCs). In the intestine, NLRP6 is highly expressed in non-hematopoietic cells such as myofibroblasts and intestinal epithelial cells, rather than hematopoietic cells such as CD45+, which regulates the composition of the intestinal flora and maintains the intestinal environment.

In NLRP6-deficient mice, it was observed that the function of NLRP6 is to inhibit the activation of NF-κB and MAPK, thereby promoting apoptosis, inhibiting inflammation and proliferation of intestinal tissues. Macrophage in NLRP6-deficient mice increased NF-κB activation during bacterial infection, accompanied by increased secretion of NF-κB and MAPK-dependent cytokines and chemokines, and a significant increase in the number of immune cells, activated by Toll Receptor (TLR), which enhances the activation of NF-κB and MAPK signaling, suggesting that NLRP6 may inhibit TLR pathway and prevent inflammation from expanding after recognition of pathogens.

Relationship between NLRP6 Protein and Disease

NLRP6 is a key component of the T cell immune response and can potentially reduce inflammation. Studies have found that chronic inflammation can develop into a tumor, and the probability of eventually developing colorectal cancer in patients with ulcerative colitis (UC) is more than 10 times that of those without chronic colonic inflammation. Studies have shown that NLRP6 can significantly alter the composition of the intestinal microflora. Loss of NLRP6 expression leads to an increase in the number of bacteria in the intestinal tract (Prevotellaceae) and TM7, which aggravates colitis. The colon epithelium self-renews every 3 to 5 days, and NLRP6 is involved in the autoregulation of the intestinal epithelium in radiation-sensitive colonic myofibroblasts. Imbalances in the mechanisms that promote intestinal repair and wound healing can lead to tumorigenesis. NLRP6 is essential for the healing of intestinal mucosal wounds, preventing the recurrence of colitis in mice and controlling the proliferation of epithelial cells after injury.

The loss of expression of NLRP6 is enhanced by the expression of multiple genes including casein kinase 1 epsilon (Csnk1ε) and Smarcc1 (SWI/SNF family members), both of which are involved in the proliferation of abnormally developing epithelium. While Csnk1ε is a phosphorylated protein involved in some key pathways of tumor progression, inhibition of Csnk1ε can arrest tumor growth. Studies have used dextran sulfate sodium (DSS)/azoxymethane (AOM) to establish a colitis/cancer model. It was found that NLRP6-deficient mice had increased susceptibility to colitis and colitis-associated tumors (CAC), tumors formed after inflammatory injury were larger, and epithelial cell proliferation time was prolonged, which was associated with the decline of IL-18 in serum and colon.

References:

Ratsimandresy, R. A. , Dorfleutner, A. , & Stehlik, C. . (2013). An update on pyrin domain-containing pattern recognition receptors: from immunity to pathology. Frontiers in Immunology, 4.
Wlodarska, M., Thaiss, C. A., Nowarski, R., Henaomejia, J., Zhang, J. P., & Brown, E. M., et al. (2014). Nlrp6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell, 156(5), 1045-1059.
Levy, M. , Shapiro, H. , Thaiss, C. A. , & Elinav, E. . (2017). Nlrp6: a multifaceted innate immune sensor. Trends in Immunology, 38(4), 248-260.

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