MEFV

MEFV encodes pyrin (also called marenostrin or TRIM20), a cytosolic innate-immune protein expressed predominantly in myeloid/granulocytic cells. Pyrin has an N-terminal PYRIN (PYD/DAPIN) domain, a central B-box-type zinc finger and coiled-coil region, and a C-terminal B30.2/SPRY (PRY-SPRY) domain; it belongs to the tripartite-motif (TRIM) family (TRIM20). Pyrin functions as an inflammasome sensor that detects pathogen-driven inactivation of the small GTPase RhoA. In the resting state, RhoA-activated kinases PKN1/PKN2 phosphorylate pyrin (Ser208/Ser242), creating docking sites for inhibitory 14-3-3 proteins that keep pyrin inactive. Loss of RhoA activity (e.g. by bacterial toxins/effectors) dephosphorylates pyrin, releases 14-3-3, and triggers assembly of the pyrin inflammasome: pyrin nucleates PYCARD/ASC speck (pyroptosome) formation through PYD-PYD interactions, activating caspase-1 and driving maturation of IL-1beta and IL-18 and pyroptotic cell death. Pyrin inflammasome activation in wild-type cells requires intact microtubules. Beyond this sensor role, pyrin also acts as a selective-autophagy receptor ("precision autophagy"): it serves as a platform that recruits ULK1, Beclin-1/BECN1, ATG16L1 and ATG8/LC3-family proteins to target inflammasome components (NLRP3, NLRP1, pro-caspase-1) for autophagic degradation, thereby restraining excessive IL-1beta/IL-18-driven inflammation. Pyrin localizes to the cytoplasm and cytoskeleton, associating with microtubules and actin filaments (perinuclear filaments, leading-edge ruffles/lamellipodia) and with ASC specks and autophagosomes; an alternatively spliced isoform lacking exon 2 translocates to the nucleus. Gain-of-function MEFV mutations, mostly in the B30.2/SPRY domain, cause autosomal-recessive Familial Mediterranean Fever (FMF), and mutations affecting the Ser242 14-3-3 site cause autosomal-dominant Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND). In addition to the established indirect route, in which RhoA inactivation by bacterial toxins removes PKN1/2-mediated phosphorylation of pyrin and releases inhibitory 14-3-3 proteins, the pyrin B30.2/SPRY domain binds the RHO-family GTPase CDC42 directly; this interaction controls pyrin localisation and the threshold for inflammasome assembly, so pyrin is regulated by two RHO-family GTPases through different mechanisms. Some pathogenic MEFV variants hyperactivate pyrin without requiring CDC42, indicating more than one activation pathway.

Disorders

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