Pyrin Activates the ASC Pyroptosome in Response to Engagement by Autoinflammatory PSTPIP1 Mutants

Abstract

The molecular mechanism by which mutations in the cytoskeleton-organizing protein PSTPIP1 cause the autoinflammatory PAPA syndrome is still elusive. Here, we demonstrate that PSTPIP1 requires the familial Mediterranean fever protein pyrin to assemble the ASC pyroptosome, a molecular platform that recruits and activates caspase-1. We provide evidence that pyrin is a cytosolic receptor for PSTPIP1. Pyrin exists as a homotrimer in an autoinhibited state due to intramolecular interactions between its pyrin domain (PYD) and B-box. Ligation by PSTPIP1, which is also a homotrimer, activates pyrin by unmasking its PYD, thereby allowing it to interact with ASC and facilitate ASC oligomerization into an active ASC pyroptosome. Because of their high binding affinity to pyrin's B-box, PAPA-associated PSTPIP1 mutants were found to be more effective than WT PSTPIP1 in inducing pyrin activation. Therefore, constitutive ligation and activation of pyrin by mutant PSTPIP1 proteins explain the autoinflammatory phenotype seen in PAPA syndrome.

Critical role for inflammasome-independent IL-1β production in osteomyelitis

“…It was discovered that the PAPA-inducing mutation in PSTPIP1 results in aberrant inflammasome activation and IL-1β-driven pathology in patients, suggesting that PSTPIP1 is a novel negative regulator of inflammasomes (23)(24)(25)(26). In line with this, IL-1 blockade therapies including Anakinra treatment have proven effective in controlling inflammatory flares in PAPA syndrome patients (27,28).…”

“…PSTPIP1, which shares marked sequence and structural homology with PSTPIP2 (19)(20)(21), has recently been identified as a negative regulator of inflammasome activation (22)(23)(24). Furthermore, inflammasome-mediated production of IL-1β by macrophages has been found to play instrumental roles in the pathogenesis of numerous autoinflammatory diseases.…”

Antiviral TRIMs: friend or foe in autoimmune and autoinflammatory disease?

“…For example, mutations in PSTPIP1 [95], that prevent interaction with pyrin, have been linked to the development of PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, Acne), an autoinflammatory condition. [96]. In addition, the known mutations in pyrin (M694A and V726A) that cause FMF have recently been described as risk alleles for development and morbidity of multiple sclerosis (MS) [97].…”

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

“…However, it is still unknown whether pyrin acts as an ASC activator, inducing inflammasome-independent IL-1b release or as negative inflammasome regulator able to dampen NLRP3 function by competing for ASC. 95,96 In both hypotheses pyrin and proline-serinethreonine phosphatase-interacting protein 1 mutations are thought to induce dysregulation of IL-1b secretion. 97 A similar hypothesis was formulated for caspase-12, which is expressed in several mammals but commonly present as a null allele in humans, where a mutation leads to a truncated non-functional form of the protein.…”