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

被引:43
作者
Finethy, Ryan [1 ]
Dockterman, Jacob [2 ]
Kutsch, Miriam [1 ]
Orench-Rivera, Nichole [3 ]
Wallace, Graham D. [1 ]
Piro, Anthony S. [1 ]
Luoma, Sarah [1 ]
Haldar, Arun K. [1 ,8 ]
Hwang, Seungmin [4 ,9 ]
Martinez, Jennifer [5 ]
Kuehn, Meta J. [3 ]
Taylor, Gregory A. [1 ,2 ,6 ,7 ]
Coers, Jorn [1 ,2 ]
机构
[1] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27708 USA
[2] Duke Univ, Dept Immunol, Med Ctr, Durham, NC 27708 USA
[3] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA
[4] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA
[5] NIEHS, Immun Inflammat & Dis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA
[6] Duke Univ, Med Ctr, Dept Med, Div Geriatr,Ctr Study Aging & Human Dev, Durham, NC 27710 USA
[7] VA Med Ctr, Geriatr Res Educ & Clin Ctr, Durham, NC USA
[8] Council Sci & Ind Res CSIR, Div Biochem, Cent Drug Res Inst CDRI, Lucknow, Uttar Pradesh, India
[9] VIR Biotechnol, San Francisco, CA USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
autophagy; caspase‐ 4; IRGM; lipopolysaccharide; noncanonical inflammasome; GUANYLATE-BINDING-PROTEINS; NONCANONICAL INFLAMMASOME ACTIVATION; INTERFERON-INDUCIBLE GTPASES; CELL-AUTONOMOUS IMMUNITY; AIM2; INFLAMMASOME; BACTERIAL LIPOPOLYSACCHARIDE; CYTOKINE PRODUCTION; NLRP3; TOXOPLASMA-GONDII; HOST-RESISTANCE;
D O I
10.15252/embr.202050830
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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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页数:17
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