title: Cutting edge: the UNC93B1 tyrosine-based motif regulates trafficking and TLR responses via separate mechanisms.
abstract: Sensing of nucleic acids by TLRs is crucial in the host defense against viruses and bacteria. Unc-93 homolog B1 (UNC93B1) regulates the trafficking of nucleic acid-sensing TLRs from the endoplasmic reticulum to endolysosomes, where the TLRs encounter their respective ligands and become activated. In this article, we show that a carboxyl-terminal tyrosine-based sorting motif (YxxΦ) in UNC93B1 differentially regulates human nucleic acid-sensing TLRs in a receptor- and ligand-specific manner. Destruction of YxxΦ abolished TLR7, TLR8, and TLR9 activity toward nucleic acids in human B cells and monocytes, whereas TLR8 responses toward small molecules remained intact. YxxΦ in UNC93B1 influenced the subcellular localization of human UNC93B1 via both adapter protein complex (AP)1- and AP2-dependent trafficking pathways. However, loss of AP function was not causal for altered TLR responses, suggesting AP-independent functions of YxxΦ in UNC93B1.
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany;
authors.forename: Karin
authors.initials: K
authors.lastname: Pelka
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany;
authors.forename: Kshiti
authors.initials: K
authors.lastname: Phulphagar
authors.affiliation: Institute of Biochemistry I and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany;
authors.forename: Jana
authors.initials: J
authors.lastname: Zimmermann
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany;
authors.forename: Rainer
authors.initials: R
authors.lastname: Stahl
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany;
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Schmid-Burgk
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Institute of Physical and Theoretical Chemistry, University of Bonn, 53121 Bonn, Germany;
authors.forename: Jan-Hendrik
authors.initials: JH
authors.lastname: Spille
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany;
authors.forename: Larisa I
authors.initials: LI
authors.lastname: Labzin
authors.affiliation: Idera Pharmaceuticals, Cambridge, MA 02139;
authors.forename: Sudhir
authors.initials: S
authors.lastname: Agrawal
authors.affiliation: Idera Pharmaceuticals, Cambridge, MA 02139;
authors.forename: Ekambar R
authors.initials: ER
authors.lastname: Kandimalla
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; Howard Hughes Medical Institute, New York, NY 10065; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Public Assistance-Paris Hospitals, 75015 Paris, France;
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany;
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655; and.
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
authors.affiliation: Institute of Biochemistry I and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Höning
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany; Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655; and German Center for Neurodegenerative Diseases, 53175 Bonn, Germany eicke.latz@uni-bonn.de.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
mesh_terms: D033961:Adaptor Protein Complex 1 / Q000235:genetics / Q000276:immunology*; D033962:Adaptor Protein Complex 2 / Q000235:genetics / Q000276:immunology*; D020816:Amino Acid Motifs; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*
chemical_list: D033961:Adaptor Protein Complex 1; D033962:Adaptor Protein Complex 2; D026901:Membrane Transport Proteins; D051193:Toll-Like Receptors; C454130:UNC93B1 protein, human