The Human NLRP1 Inflammasome

The inflammasome is an essential arm of the innate immune system which aims to clear the organism of pathogens (stranger) or resolve cellular stresses (danger). It is a multi-protein complex that is triggered by infections and/or physiological danger-associated signals. Upon activation, it induces an inflammatory form of cell death known as pyroptosis.  While its function can be essential in certain contexts, the inflammasome will become harmful if improperly solicited.

Inflammasome activation is initiated by “sensor” molecules belonging to the Nod-like receptor (NLR) family of intracellular danger/pathogen-associated molecular pattern (DAMP/PAMP) receptors. NLR family pyrin domain containing 1 (NLRP1) was the first NLR protein identified with the ability to initiate inflammasome assembly. 

While highly potent in its actions, dysregulation of the NLRP1 inflammasomes results in  several Mendelian inflammatory disorders.  Germline mutations in NLRP1 itself or in direct interacting proteins such as DPP9, have been found to cause constitutive inflammasome activation that underlie human diseases such as Multiple Self-Healing Palmoplantar Carcinoma (MSPC, MIM615225), Familial Keratosis Lichenoides Chronica (FKLC, MIM606636), Auto-inflammation with Arthritis and Dyskeratosis (AIADK, MIM617388), Juvenile Recurrent Respiratory Papillomatosis (JRRP, MIM618803) and Hatipoglu Syndrome (MIM620331). MSPC and FKLC patients present with multiple epithelial lesions consistent with focal dyskeratosis and local inflammation, and a marked pre-disposition to cutaneous squamous cell carcinomas.