title: A promiscuous lipid-binding protein diversifies the subcellular sites of toll-like receptor signal transduction.
abstract: The Toll-like receptors (TLRs) of the innate immune system are unusual in that individual family members are located on different organelles, yet most activate a common signaling pathway important for host defense. It remains unclear how this common signaling pathway can be activated from multiple subcellular locations. Here, we report that, in response to natural activators of innate immunity, the sorting adaptor TIRAP regulates TLR signaling from the plasma membrane and endosomes. TLR signaling from both locations triggers the TIRAP-dependent assembly of the myddosome, a protein complex that controls proinflammatory cytokine expression. The actions of TIRAP depend on the promiscuity of its phosphoinositide-binding domain. Different lipid targets of this domain direct TIRAP to different organelles, allowing it to survey multiple compartments for the presence of activated TLRs. These data establish how promiscuity, rather than specificity, can be a beneficial means of diversifying the subcellular sites of innate immune signal transduction.
authors: Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors: Kevin S
authors: KS
authors: Bonham
authors: Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors: Megan H
authors: MH
authors: Orzalli
authors: Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA.
authors: Kachiko
authors: K
authors: Hayashi
authors: The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
authors: Amaya I
authors: AI
authors: Wolf
authors: Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors: Christoph
authors: C
authors: Glanemann
authors: Immune Imaging Program, The Centenary Institute, Locked Bag 6, Newtown, NSW 2042, Australia; Discipline of Dermatology, University of Sydney, NSW 2006, Australia.
authors: Wolfgang
authors: W
authors: Weninger
authors: Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA.
authors: Akiko
authors: A
authors: Iwasaki
authors: Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors: David M
authors: DM
authors: Knipe
authors: Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: jonathan.kagan@childrens.harvard.edu.
authors: Jonathan C
authors: JC
authors: Kagan
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D006561:Herpes Simplex / Q000276:immunology; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; D051193:Toll-Like Receptors