Pyrin (MEFV)

Pyrin is a cytosolic protein encoded by the MEFV gene that plays a pivotal role in the innate immune system as a pattern recognition receptor [4, 13]. It is primarily expressed in granulocytes and monocytes, where it monitors cellular homeostasis by sensing the inactivation of RhoA GTPases, a common effect of various bacterial toxins [7, 15]. Upon detecting RhoA inhibition, pyrin undergoes dephosphorylation and recruits the adaptor protein ASC and pro-caspase-1 to form the pyrin inflammasome [5, 10]. This complex facilitates the maturation and release of pro-inflammatory cytokines, specifically interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), and can trigger pyroptotic cell death [1, 10]. Mutations in the MEFV gene are the underlying cause of Familial Mediterranean Fever (FMF) and other autoinflammatory syndromes, leading to uncontrolled or hypersensitive inflammasome activation [4, 7]. Colchicine is the standard treatment for these conditions, as it prevents inflammasome assembly by inhibiting microtubule polymerization [3, 12]. In cases where colchicine is ineffective, biological agents that target the downstream IL-1 pathway are used to mitigate the resulting systemic inflammation [3, 5].

Other names

Marenostrin [13]TRIM20 [4]Mediterranean fever protein [14]Tripartite motif-containing protein 20 [13]

Colchicine inhibits microtubule polymerization, which is essential for the assembly and activation of the pyrin inflammasome [3, 12, 17]. IL-1 inhibitors (Anakinra, Canakinumab, Rilonacept) act downstream by blocking the signaling of IL-1β, the primary cytokine product of the pyrin inflammasome pathway [3, 5].