The
pyrin inflammasome has evolved as an innate immune sensor to detect
bacterial toxin-induced Rho
guanosine triphosphatase (
Rho GTPase)-inactivation, a process that is similar to the "guard" mechanism in plants.
Rho GTPases act as molecular switches to regulate a variety of signal transduction pathways including cytoskeletal organization. Pathogens can modulate
Rho GTPase activity to suppress host immune responses such as phagocytosis.
Pyrin is encoded by MEFV, the gene that is mutated in patients with
familial Mediterranean fever (FMF). FMF is the prototypic autoinflammatory disease characterized by recurring short episodes of systemic
inflammation and is a common disorder in many populations in the Mediterranean basin.
Pyrin specifically senses modifications in the activity of the
small GTPase RhoA, which binds to many effector
proteins including the
serine/threonine-protein kinases PKN1 and PKN2 and
actin-binding proteins. RhoA activation leads to PKN-mediated phosphorylation-dependent
pyrin inhibition. Conversely, pathogen
virulence factors downregulate RhoA activity in a variety of ways, and these changes are detected by the
pyrin inflammasome irrespective of the type of modifications. MEFV pathogenic variants favor the active state of
pyrin and elicit proinflammatory
cytokine release and pyroptosis. They can be inherited either as a dominant or recessive trait depending on the variant's location and effect on the
protein function. Mutations in the C-terminal B30.2 domain are usually considered recessive, although heterozygotes may manifest a biochemical or even a clinical phenotype. These variants are hypomorphic in regard to their effect on intramolecular interactions, but ultimately accentuate
pyrin activity. Heterozygous mutations in other domains of
pyrin affect residues critical for inhibition or
protein oligomerization, and lead to constitutively active
inflammasome. In healthy carriers of FMF mutations who have the subclinical inflammatory phenotype, the increased activity of
pyrin might have been protective against endemic
infections over human history. This finding is supported by the observation of high carrier frequencies of FMF-mutations in multiple populations. The
pyrin inflammasome also plays a role in mediating
inflammation in other autoinflammatory diseases linked to dysregulation in the actin polymerization pathway. Therefore, the assembly of the
pyrin inflammasome is initiated in response to fluctuations in cytoplasmic homeostasis and perturbations in cytoskeletal dynamics.