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

Immunity. 2015 Aug 18;43(2):264-76. doi: 10.1016/j.immuni.2015.07.018. Epub 2015 Aug 11.

Abstract

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 for the maintenance of 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 POP1, 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 signaling, and we propose that POP1 provides a regulatory feedback loop that shuts down excessive inflammatory responses and thereby prevents systemic inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Caspase 1 / metabolism
  • Cell Line
  • Cryopyrin-Associated Periodic Syndromes / immunology*
  • Dendritic Cells / immunology*
  • Female
  • Gene Expression Regulation / genetics
  • Homeostasis
  • Humans
  • Inflammasomes / metabolism*
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / immunology
  • Macrophages, Peritoneal / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Monocytes / immunology*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Peritonitis / chemically induced
  • Peritonitis / immunology*
  • Protein Multimerization / genetics
  • RNA, Small Interfering / genetics
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism*

Substances

  • Carrier Proteins
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Pop1 protein, mouse
  • RNA, Small Interfering
  • Ribonucleoproteins
  • Caspase 1