title: Lysosomal trafficking regulator Lyst links membrane trafficking to toll-like receptor-mediated inflammatory responses.
abstract: Subcellular compartmentalization of receptor signaling is an emerging principle in innate immunity. However, the functional integration of receptor signaling pathways into membrane trafficking routes and its physiological relevance for immune responses is still largely unclear. In this study, using Lyst-mutant beige mice, we show that lysosomal trafficking regulator Lyst links endolysosomal organization to the selective control of toll-like receptor 3 (TLR3)- and TLR4-mediated proinflammatory responses. Consequently, Lyst-mutant mice showed increased susceptibility to bacterial infection and were largely resistant to endotoxin-induced septic shock. Mechanistic analysis revealed that Lyst specifically controls TLR3- and TLR4-induced endosomal TRIF (TIR domain-containing adapter-inducing interferon β) signaling pathways. Loss of functional Lyst leads to dysregulated phagosomal maturation, resulting in a failure to form an activation-induced Rab7+endosomal/phagosomal compartment. This specific Rab7+compartment was further demonstrated to serve as a major site for active TRIF signaling events, thus linking phagosomal maturation to specific TLR signaling pathways. The immunoregulatory role of Lyst on TLR signaling pathways was confirmed in human cells by CRISPR/Cas9-mediated gene inactivation. As mutations in LYST cause human Chédiak-Higashi syndrome, a severe immunodeficiency, our findings also contribute to a better understanding of human disease mechanisms.
authors.affiliation: Institute of Clinical Chemistry, Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Andreas
authors.identifier: 0000-0002-4642-8278
authors.initials: A
authors.lastname: Westphal
authors.affiliation: Institute of Clinical Chemistry, Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Weijia
authors.identifier: 0000-0003-1565-6929
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Institute of Clinical Chemistry, Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Jinbo
authors.identifier: 0000-0002-0788-8693
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Guntram
authors.identifier: 0000-0003-3718-2090
authors.initials: G
authors.lastname: Grassl
authors.affiliation: Institute of Clinical Chemistry, Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Krautkrämer
authors.affiliation: Division of Structural Biochemistry, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, 23845 Borstel, Germany.
authors.forename: Otto
authors.identifier: 0000-0002-5049-119X
authors.initials: O
authors.lastname: Holst
authors.affiliation: Institute of Clinical Chemistry, Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany Lee.Kyeong-Hee@mh-hannover.de Foeger.Niko@mh-hannover.de.
authors.forename: Niko
authors.identifier: 0000-0002-1022-7108
authors.initials: N
authors.lastname: Föger
authors.affiliation: Institute of Clinical Chemistry, Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany Lee.Kyeong-Hee@mh-hannover.de Foeger.Niko@mh-hannover.de.
authors.forename: Kyeong-Hee
authors.identifier: 0000-0002-9455-4201
authors.initials: KH
authors.lastname: Lee
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D007249:Inflammation / Q000209:etiology*; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D010588:Phagosomes / Q000502:physiology; D011506:Proteins / Q000502:physiology*; D012772:Shock, Septic / Q000517:prevention & control; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology*; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins / Q000502:physiology; D000090802:rab7 GTP-Binding Proteins
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D011506:Proteins; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; C491133:Lyst protein, mouse; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse