Pyrin (also known as Mediterranean fever protein) (MEFV)

Pyrin (protein encoded by the MEFV gene) is a cytosolic sensor protein mainly expressed in white blood cells involved in the innate immune response, including neutrophils, eosinophils, monocytes, and dendritic cells[2][4]. It is a member of the TRIM family and contains a unique PYD domain, essential for binding to the adaptor protein ASC and recruiting caspase-1 for IL-1β/IL-18 maturation[1][3][4]. Pyrin regulates inflammation by sensing modifications to the cytoskeletal GTPase RhoA, serving as a pattern recognition receptor for dangerous cellular disturbances, particularly those caused by pathogens[1][4]. Activation of the pyrin inflammasome drives secretion of proinflammatory cytokines and pyroptotic cell death, underpinning the pathogenesis of several autoinflammatory syndromes, most notably familial Mediterranean fever (FMF)[1][2][4]. Disease-associated mutations, especially in the C-terminal B30.2 domain, often confer gain-of-function and promote unrestrained pyrin activity, leading to excessive and inappropriate inflammation. Colchicine remains a frontline therapy, and IL-1 blockade is used in colchicine-resistant cases[2][4]. The protein interacts with multiple signaling and cytoskeletal partners (ASC, caspase-1, PKN1/2, 14-3-3 proteins), and its activity is tightly regulated by phosphorylation and oligomerization[4]. Defective regulation or pathogenic mutations result in recurrent fevers, serositis, and increased risk of amyloidosis, characteristic of FMF.

Other names

MarenostrinTRIM20FMFMEFPAANDPyrin innate immunity regulatorMediterranean fever proteinPyrin inflammasome regulatorMarenostrin/TRIM20

- **Colchicine:** Inhibits microtubule polymerization, thereby preventing pyrin inflammasome activation[2][4]. - **IL-1 inhibitors:** Block inflammatory downstream signaling of pyrin-induced IL-1β secretion[4]. - **Steroid hormone catabolites (in vitro):** Pregnanolone and etiocholanaolone may activate pyrin via interaction with B30.2 domain[2].