Dynamin-related Irgm proteins modulate LPS-induced caspase-11 activation and septic shock
| Autor: | Nichole Orench-Rivera, Miriam Kutsch, Gregory A. Taylor, Seungmin Hwang, Ryan Finethy, Anthony S. Piro, Jennifer Martinez, Sarah Luoma, Arun K. Haldar, Jacob Dockterman, Graham D. Wallace, Meta J. Kuehn, Jörn Coers |
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| Rok vydání: | 2020 |
| Předmět: |
Dynamins
Lipopolysaccharides Bacterial outer membrane vesicles Lipopolysaccharide Inflammasomes Caspase 4 Caspase-11 Biochemistry 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Genetics Extracellular Animals News & Views Molecular Biology 030304 developmental biology Dynamin 0303 health sciences biology Chemistry Articles Shock Septic Caspases Initiator Cell biology Caspases IRGM biology.protein TLR4 lipids (amino acids peptides and proteins) 030217 neurology & neurosurgery |
| Zdroj: | EMBO Rep |
| ISSN: | 1469-3178 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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