Pyrin and ASC Co-Localize to Cellular Sites that Are Rich in Polymerizing Actin

Abstract

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations in the MEFV locus, which encodes the protein pyrin. While it is known that pyrin is expressed in myeloid cells and several fibroblastic cell types, the exact function of pyrin in these cells and the mechanism underlying the pathological effect of pyrin mutations have yet to be revealed. Here, we document that in migrating human monocytes, pyrin protein is dramatically polarized at the leading edge, where it co-localizes with polymerizing actin. ASC (Apoptosis-associated Speck protein with CARD domain), a known pyrin-interacting protein and a critical component of the inflamma-some, is also located at the leading edge in migrating monocytes. Similarly, both pyrin and ASC concentrate in dynamically polymerizing actin-rich tails generated by Listeria monocytogenes. Pyrin's B-box and coiled-coil region is required for its association with Listeria tails. Pyrin also binds, with low affinity and via the same domains, to actin, VASP, and Arp3. Though disease-causing mutations in pyrin do not appear to alter its localization to the leading edge or to Listeria rocket tails, they could potentially have important functional consequences in the context of processes such as migration and cell synapse formation. The co-localization of pyrin and ASC together at such sites may provide an important link between cytoskeletal signaling and inflammasome function.

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

“…These studies revealed that pyrin exists as a homotrimer in unstimulated cells and that stimulation releases an autoinhibitory interaction between the N terminal SPRY domain of pyrin and its B box. This now frees the SPRY domain of pyrin to facilitate interaction with ASC and thus promote activation of the inflammasome [94]. These studies concur with the phenotype of mice expressing the pyrin domain alone which show enhanced IL-1β processing, whereas full length pyrin inhibits these responses.…”

“…Inflammatory stimuli results in the release of an autoinhibitory interaction between pyrins N terminal SPRY domain and its B box domain. Once activated, the SPRY domain then interacts with ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) promoting its oligomerisation and activation of the inflammasome [94,112].…”

Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β

“…Subsequent work showed that this protein formed an inflammasome complex for the activation of IL-1 and IL-18 and that it is also an actin-binding protein (Mansfield et al, 2001;Richards et al, 2001;Waite et al, 2009). We now show that a lack of actin depolymerization triggers the pyrin inflammasome in vivo, using a mouse model of autoinflammatory disease.…”

“…It is tempting to speculate that the trigger is some modified form of actin given that pyrin binds to, and colocalizes with, polymerizing actin (Mansfield et al, 2001;Richards et al, 2001;Waite et al, 2009). However, further work is required to investigate this interaction.…”

“…Interestingly, pyrin interacts with ASC, microtubules, and actin filaments (Mansfield et al, 2001;Richards et al, 2001;Waite et al, 2009), and it has recently been shown that modification of RhoGTPases by bacterial toxins can trigger the pyrin inflammasome, perhaps via modulation of actin dynamics (Xu et al, 2014). This raises the fascinating prospect of a link between perturbations in the actin cytoskeleton and autoinflammatory disease.…”