NLRP12 Gene

The NLRP12 gene (NLRP12 stands for "NLR Family Pyrin Domain Containing 12") is a protein-coding gene located on chromosome 19q13.42. The NLRP12 gene encodes a member of the so-called CATERPILLER family (older name for NLR proteins) of cytoplasmic proteins.

A new class of (systemic) autoinflammatory syndromes (SAIDs) are referred to as NLRP12-associated diseases (NLRP12AD). The etiopathology of this special group of diseases is based on mutations in the NLRP12 gene. Excessive increases in IL-1beta secretion (80-175 fold) cause the inflammatory symptoms of the disease. In these patients, a dramatic improvement in symptoms can be achieved with Anakinra.

The encoded NLRP12 protein, which contains an N-terminal pyrin domain, a NACHT domain, a NACHT-associated domain and a C-terminal leucine-rich repeat region, acts as an anti-inflammatory factor by suppressing inflammatory reactions in activated monocytes.

Mutations in this gene, which cause a deficiency of the encoded protein, cause familial autoinflammatory cold syndrome type 2 (see below Familial cold urticaria).

The encoded NLRP12 protein is mainly expressed in dendritic cells and macrophages and inhibits both canonical and non-canonical NF-kappa-B and ERK activation pathways. It acts as a negative regulator of NOD2 by driving its degradation via the proteasome pathway. In turn, the encoded protein promotes bacterial tolerance.

Furthermore, NLRP12 inhibits DDX58-mediated immune signaling against RNA viruses by reducing 'Lys-63'-linked DDX58 activation mediated by the E3 ubiquitin ligase TRIM25, but enhancing 'Lys-48'-linked DDX58 degradation mediated by the E3 ubiquitin ligase RNF125. Also acts as a negative regulator of the inflammatory response to mitigate obesity and obesity-associated diseases in adipose tissue.

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