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Dynamin-related Irgm proteins modulate LPS-induced caspase-11 activation and septic shock.

Publication ,  Journal Article
Finethy, R; Dockterman, J; Kutsch, M; Orench-Rivera, N; Wallace, GD; Piro, AS; Luoma, S; Haldar, AK; Hwang, S; Martinez, J; Kuehn, MJ ...
Published in: EMBO Rep
November 5, 2020

Inflammation associated with gram-negative bacterial infections is often instigated by the bacterial cell wall component lipopolysaccharide (LPS). LPS-induced inflammation and resulting life-threatening sepsis are mediated by the two distinct LPS receptors TLR4 and caspase-11 (caspase-4/-5 in humans). Whereas the regulation of TLR4 activation by extracellular and phago-endosomal LPS has been studied in great detail, auxiliary host factors that specifically modulate recognition of cytosolic LPS by caspase-11 are largely unknown. This study identifies autophagy-related and dynamin-related membrane remodeling proteins belonging to the family of Immunity-related GTPases M clade (IRGM) as negative regulators of caspase-11 activation in macrophages. Phagocytes lacking expression of mouse isoform Irgm2 aberrantly activate caspase-11-dependent inflammatory responses when exposed to extracellular LPS, bacterial outer membrane vesicles, or gram-negative bacteria. Consequently, Irgm2-deficient mice display increased susceptibility to caspase-11-mediated septic shock in vivo. This Irgm2 phenotype is partly reversed by the simultaneous genetic deletion of the two additional Irgm paralogs Irgm1 and Irgm3, indicating that dysregulated Irgm isoform expression disrupts intracellular LPS processing pathways that limit LPS availability for caspase-11 activation.

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Published In

EMBO Rep

DOI

EISSN

1469-3178

Publication Date

November 5, 2020

Volume

21

Issue

11

Start / End Page

e50830

Location

England

Related Subject Headings

  • Shock, Septic
  • Mice
  • Lipopolysaccharides
  • Inflammasomes
  • Dynamins
  • Developmental Biology
  • Caspases, Initiator
  • Caspases
  • Animals
  • 3101 Biochemistry and cell biology
 

Citation

APA
Chicago
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Finethy, R., Dockterman, J., Kutsch, M., Orench-Rivera, N., Wallace, G. D., Piro, A. S., … Coers, J. (2020). Dynamin-related Irgm proteins modulate LPS-induced caspase-11 activation and septic shock. EMBO Rep, 21(11), e50830. https://doi.org/10.15252/embr.202050830
Finethy, Ryan, Jacob Dockterman, Miriam Kutsch, Nichole Orench-Rivera, Graham D. Wallace, Anthony S. Piro, Sarah Luoma, et al. “Dynamin-related Irgm proteins modulate LPS-induced caspase-11 activation and septic shock.EMBO Rep 21, no. 11 (November 5, 2020): e50830. https://doi.org/10.15252/embr.202050830.
Finethy R, Dockterman J, Kutsch M, Orench-Rivera N, Wallace GD, Piro AS, et al. Dynamin-related Irgm proteins modulate LPS-induced caspase-11 activation and septic shock. EMBO Rep. 2020 Nov 5;21(11):e50830.
Finethy, Ryan, et al. “Dynamin-related Irgm proteins modulate LPS-induced caspase-11 activation and septic shock.EMBO Rep, vol. 21, no. 11, Nov. 2020, p. e50830. Pubmed, doi:10.15252/embr.202050830.
Finethy R, Dockterman J, Kutsch M, Orench-Rivera N, Wallace GD, Piro AS, Luoma S, Haldar AK, Hwang S, Martinez J, Kuehn MJ, Taylor GA, Coers J. Dynamin-related Irgm proteins modulate LPS-induced caspase-11 activation and septic shock. EMBO Rep. 2020 Nov 5;21(11):e50830.
Journal cover image

Published In

EMBO Rep

DOI

EISSN

1469-3178

Publication Date

November 5, 2020

Volume

21

Issue

11

Start / End Page

e50830

Location

England

Related Subject Headings

  • Shock, Septic
  • Mice
  • Lipopolysaccharides
  • Inflammasomes
  • Dynamins
  • Developmental Biology
  • Caspases, Initiator
  • Caspases
  • Animals
  • 3101 Biochemistry and cell biology