Interaction between Pyrin and the Apoptotic Speck Protein (ASC) Modulates ASC-induced Apoptosis

Abstract

Patients with familial Mediterranean fever suffer sporadic inflammatory attacks characterized by fever and intense pain (in joints, abdomen, or chest). Pyrin, the product of the MEFV locus, is a cytosolic protein whose function is unknown. Using pyrin as a "bait" to probe a yeast two-hybrid library made from neutrophil cDNA, we isolated apoptotic speck protein containing a caspase recruitment domain (CARD) (ASC), a proapoptotic protein that induces the formation of large cytosolic "specks" in transfected cells. We found that when HeLa cells are transfected with ASC, specks are formed. After co-transfection of cells with ASC plus wild type pyrin, an increase in speck-positive cells is found, and speck-positive cells show increased survival. Immunofluorescence studies show that pyrin co-localizes with ASC in specks. Speck localization requires exon 1 of pyrin, but exon 1 alone of pyrin does not result in an increase in the number of specks. Exon 1 of pyrin and exon 1 of ASC show 42% sequence similarity and resemble death domain-related structures in modeling studies. These findings link pyrin to apoptosis pathways and suggest that the modulation of cell survival may be a component of the pathophysiology of familial Mediterranean fever.

Dual role of TMS1/ASC in death receptor signaling

“…TMS1 may be another example of an NF-kB/JNK-regulated factor that functions in a proapoptotic capacity. Previous work from our lab and others has shown that TMS1 induces apoptosis when overexpressed (Masumoto et al, 1999;McConnell and Vertino, 2000;Richards et al, 2001;Ohtsuka et al, 2004). This apoptosis can be blocked by dominant negative mutants of caspase-9 and is dependent on Bax, implicating the mitochondrial pathway Ohtsuka et al, 2004).…”

Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization

“…Pyrin has been shown to interact with ASC, 18 but whether this interaction leads to potentiation or inhibition of caspase-1 activation is still unclear. Based on evidence that a C-terminal truncation of pyrin in mice increased IL-1b processing while ectopic expression of WT pyrin in mouse RAW cells impaired IL-1b processing, a recent study proposed that the physiological function of pyrin is to inhibit the proteolytic activation of caspase-1 by sequestering ASC and preventing its interactions with caspase-1.…”

The estrogen-responsive B box protein: a novel enhancer of interleukin-1β secretion

“…The inflammasome component Asc has been described as an activator of procaspase-1 21 or as a modulator, leading to activation of procaspase-1 at low and inhibition at higher concentrations. 30 As the EBBP homolog Pyrin binds to Asc, 20 we tested if this is also the case for EBBP. Therefore, we performed co-IPs of HA-tagged EBBP and Asc fusion proteins tagged with an epitope of the vesicular stomatitis virus (VSV) or with a Flag tag.…”

“…This could prevent binding of procaspase-1 to Asc and its activation. 19,20 However, the strength and significance of a binding of Pyrin to Asc is controversial. 21 It is not known how the disease-causing mutations, which locate mainly to the carboxy-terminal RFP (SPRY; B30.2) domain, influence the amino-terminal pyrin domain.…”