The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease

Abstract

SUMMARY In response to infections and tissue damage, ASC-containing inflammasome protein complexes are assembled that promote caspase-1 activation, IL-1β and IL-18 processing and release, pyroptosis, and the release of ASC particles. However, excessive or persistent activation of the inflammasome causes inflammatory diseases. Therefore, a well-balanced inflammasome response is crucial to maintain homeostasis. We show that the PYD-only protein POP1 inhibited ASC-dependent inflammasome assembly by preventing inflammasome nucleation, and consequently interfered with caspase-1 activation, IL-1β and IL-18 release, pyroptosis and the release of ASC particles. There is no mouse ortholog for the POP1 gene, but transgenic expression of human POP1 in monocytes, macrophages and dendritic cells protected mice from systemic inflammation triggered by molecular PAMPs, inflammasome component NLRP3 mutation and ASC danger particles. POP1 expression was regulated by TLR- and IL-1R–signalling, and we propose that POP1 provides a regulatory feedback loop that shuts down excessive inflammatory responses and thereby prevents systemic inflammation.

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

“…30 A20-driven ubiquitination of NLRP3, PYRIN domain-only protein POP1-dependent inhibition of inflammasome assembly, or reactive oxygen species-driven suppression of caspase-1 are just three such regulatory mechanisms. [31][32][33] Figure 2. Inflammasome activation in dendritic cells and macrophages involves numerous elements.…”

The Duality of AIM2 Inflammasome: A Focus on its Role in Autoimmunity and Skin Diseases

“…Inhibiting AIM2 inflammasome activity using synthetic inhibitors, such as synthetic Oligodeoxynucleotides (ODN) containing suppressive TTAGGG Motifs (Kaminski et al, 2013) or taking advantage of endogenous AIM2 inhibitors, such as the pyrin-containing proteins, recently described by (Khare et al, 2014;de Almeida et al, 2015), or antimicrobial cathelicidin peptides, reported by Schauber and colleagues , could certainly be explored and studied for their potential to limit undesired inflammation (Man et al, 2016). Still, further research aiming at the discovery of new small-molecules to inhibit AIM2 inflammasome would certainly be of benefit to the development of effective drugs to treat chronic diseases, in which inflammation is the key player.…”

POPsicle for Fever! Cooling Down the Inflammasome

“…In this issue of Immunity, de Almeida et al (2015) report that the PYRIN domain-only protein (POP1) efficiently inhibits inflammasome activation, identifying it as a pan-inflammasome inhibitor.…”

“…In the article by de Almeida et al (2015) appearing in this issue of Immunity, the authors have identified PYRIN (PYD) only protein (POP1) as a negative regulator of inflammasome activation. Although the POP family of proteins was identified in humans more than 10 years ago (they are not found in mice) and includes POP1 (also known as ASC2), POP2, POP3, and POP4 (Stehlik et al, 2003), their functions have been unclear.…”

“…Furthermore, the authors found that POP1 overexpression inhibited ASC particle release, thereby preventing secondary inflammasome activation after engulfment by macrophages. de Almeida et al (2015) generated transgenic mice expressing human POP1 under the macrophagespecific CD68 promoter and showed that NLRP3 inflammasome autoactivation by CAPS mutation was significantly inhibited. More importantly, these mice were protected against LPS-induced peritonitis.…”