title: Phospholipid scramblase 1 regulates Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells.
abstract: Toll-like receptor 9 (TLR9) senses microbial DNA in the endosomes of plasmacytoid dendritic cells (pDCs) and triggers MyD88-dependent type I interferon (IFN) responses. To better understand TLR9 biology in pDCs, we established a yeast two-hybrid library for the identification of TLR9-interacting proteins. Here, we report that an IFN-inducible protein, phospholipid scramblase 1 (PLSCR1), interacts with TLR9 in pDCs. Knockdown of PLSCR1 expression by siRNA in human pDC cell line led to a 60-70% reduction of IFN-α responses following CpG-ODN (oligodeoxynucleotide) stimulation. Primary pDCs from PLSCR1-deficient mice produced lower amount of type 1 IFN than pDCs from the wild-type mice in response to CpG-ODN, herpes simplex virus and influenza A virus. Following CpG-A stimulation, there were much lower amounts of TLR9 in the early endosomes together with CpG-A in pDCs from PLSCR1-deficient mice. Our study demonstrates that PLSCR1 is a TLR9-interacting protein that plays an important role in pDC's type 1 IFN responses by regulating TLR9 trafficking to the endosomal compartment.
authors.affiliation: Department of Immunology, Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Amjad H
authors.initials: AH
authors.lastname: Talukder
authors.forename: Musheng
authors.initials: M
authors.lastname: Bao
authors.forename: Tae Whan
authors.initials: TW
authors.lastname: Kim
authors.forename: Valeria
authors.initials: V
authors.lastname: Facchinetti
authors.forename: Shino
authors.initials: S
authors.lastname: Hanabuchi
authors.forename: Laura
authors.initials: L
authors.lastname: Bover
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zal
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: C408982:CPG-oligonucleotide; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D016898:Interferon-alpha; C494235:Irf7 protein, mouse; D009838:Oligodeoxyribonucleotides; D049294:Phospholipid Transfer Proteins; C493426:Plscr1 protein, mouse; D051217:Toll-Like Receptor 9