Activation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation

Nat Commun. 2014;5:3209. doi: 10.1038/ncomms4209.

Abstract

Despite its clinical importance in infection and autoimmunity, the activation mechanisms of the NLRP1b inflammasome remain enigmatic. Here we show that deletion of the inflammasome adaptor ASC in BALB/c mice and in C57BL/6 macrophages expressing a functional NLRP1b prevents anthrax lethal toxin (LeTx)-induced caspase-1 autoproteolysis and speck formation. However, ASC(-/-) macrophages undergo normal LeTx-induced pyroptosis and secrete significant amounts of interleukin (IL)-1β. In contrast, ASC is critical for caspase-1 autoproteolysis and IL-1β secretion by the NLRC4, NLRP3 and AIM2 inflammasomes. Notably, LeTx-induced inflammasome activation is associated with caspase-1 ubiquitination, which is unaffected in ASC-deficient cells. In vivo, ASC-deficient mice challenged with LeTx produce significant levels of IL-1β, IL-18 and HMGB1 in circulation, although caspase-1 autoproteolysis is abolished. As a result, ASC(-/-) mice are sensitive to rapid LeTx-induced lethality. Together, these results demonstrate that ASC-driven caspase-1 autoprocessing and speck formation are dispensable for the activation of caspase-1 and the NLRP1b inflammasome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Bacterial
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Bacterial Toxins
  • CARD Signaling Adaptor Proteins
  • Caspase 1 / metabolism*
  • Cell Death
  • Female
  • HMGB1 Protein / blood
  • Inflammasomes / metabolism*
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Macrophages / metabolism
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Proteolysis*
  • Spleen / metabolism
  • Ubiquitination

Substances

  • Antigens, Bacterial
  • Apoptosis Regulatory Proteins
  • Bacterial Toxins
  • CARD Signaling Adaptor Proteins
  • HMGB1 Protein
  • HMGB1 protein, mouse
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Nalp1b protein, mouse
  • Pycard protein, mouse
  • anthrax toxin
  • Caspase 1