Irgm2 and Gate‐16 put a break on caspase‐11 activation. (1st November 2020)

• Record Type: Journal Article
• Authors: Linder, Andreas; Hornung, Veit
• Is Part Of: EMBO reports. Volume 21:Number 11(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-11-01
• Subjects: Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202051787
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract : In infections caused by gram‐negative bacteria, the bacterial cell wall component lipopolysaccharide (LPS) acts as a potent pathogen‐associated molecular pattern (PAMP) that triggers the innate immune system. This is accomplished by two pattern recognition receptor systems. Toll‐like receptor 4 (TLR4) senses extracellular LPS and induces a broad pro‐inflammatory transcriptional program and also antiviral interferons. A complementary system detects intracellular LPS. As such, upon its release into the cytoplasm, LPS can directly engage the protease caspase‐4 (caspase‐11 in the murine system) and thereby trigger a pro‐inflammatory cell death program known as pyroptosis (Rathinam et al, 2019). This is mediated by active caspase‐4 cleaving its substrate gasdermin D (GSDMD). The thereby released N‐terminal fragment of GSDMD inserts into the cell membrane and forms a cytotoxic pore. As a consequence, the cell ruptures and releases its pro‐inflammatory content. In addition, the GSDMD pore results in potassium efflux that can activate the NLRP3 inflammasome. NLRP3 in turn activates caspase‐1, which matures pro‐IL‐1β and pro‐IL‐18, further perpetuating the inflammatory nature of this cell death. Given its unconventional mode of NLRP3 activation, this pathway has been coined the non‐canonical inflammasome. Abstract : Non‐canonical inflammasome activation is crucial to mount an immune response against bacteria. Two studies in this issue show that the IFN‐inducible protein Irgm2 and the ATG8 family member Gate‐16 cooperatively limit the non‐canonical inflammasome.