title: ARC Syndrome-Linked Vps33B Protein Is Required for Inflammatory Endosomal Maturation and Signal Termination.
abstract: Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) sense microbial ligands and initiate signaling to induce inflammatory responses. Although the quality of inflammatory responses is influenced by internalization of TLRs, the role of endosomal maturation in clearing receptors and terminating inflammatory responses is not well understood. Here, we report that Drosophila and mammalian Vps33B proteins play critical roles in the maturation of phagosomes and endosomes following microbial recognition. Vps33B was necessary for clearance of endosomes containing internalized PRRs, failure of which resulted in enhanced signaling and expression of inflammatory mediators. Lack of Vps33B had no effect on trafficking of endosomes containing non-microbial cargo. These findings indicate that Vps33B function is critical for determining the fate of signaling endosomes formed following PRR activation. Exaggerated inflammatory responses dictated by persistence of receptors in aberrant endosomal compartments could therefore contribute to symptoms of ARC syndrome, a disease linked to loss of Vps33B.
authors: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Mohammed Ali
authors: MA
authors: Akbar
authors: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Rajakumar
authors: R
authors: Mandraju
authors: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Charles
authors: C
authors: Tracy
authors: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Wei
authors: W
authors: Hu
authors: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: chandrashekhar.pasare@utsouthwestern.edu.
authors: Chandrashekhar
authors: C
authors: Pasare
authors: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: helmut.kramer@utsouthwestern.edu.
authors: Helmut
authors: H
authors: Krämer
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001176:Arthrogryposis / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D002779:Cholestasis / Q000235:genetics / Q000276:immunology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D004927:Escherichia coli Infections / Q000276:immunology*; D055786:Gene Knockout Techniques; D007249:Inflammation / Q000276:immunology*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D051437:Renal Insufficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4; C000601834:VPS33B protein, mouse; D033921:Vesicular Transport Proteins; C000622651:Vps33B protein, Drosophila
keywords: ARC syndrome; LPS; Phagocytosis; TLR signaling; Tolerance