Cutting Edge: The UNC93B1 Tyrosine-Based Motif Regulates Trafficking and TLR Responses via Separate Mechanisms

• DOI: 10.4049/jimmunol.1301886
• Publication Date: 2014-09-04T14:42:39Z
• Authors: Karin Pelka; Kshiti Phulphagar; Jana Zimmermann; Rainer Stahl; Jonathan L Schmid...; Tobias Schmidt; Jan-Hendrik Spille; Larisa I Labzin; Sudhir Agrawal; Ekambar R Kandimalla; Jean-Laurent Casa...; Veit Hornung; Ann Marshak-Roths...; Stefan Höning; Eicke Latz
• Keywords: 0301 basic medicine; genetics [Adaptor Protein Complex 2]; UNC93B1 protein, human; Immunology; Adaptor Protein Complex 1; Amino Acid Motifs; Adaptor Protein Complex 2; immunology [Adaptor Protein Complex 2]; immunology [Membrane Transport Proteins]; Monocytes; genetics [Toll-Like Receptors]; immunology [Monocytes]; 03 medical and health sciences; Cell Line, Tumor; Humans; ddc:610; genetics [Adaptor Protein Complex 1]; B-Lymphocytes; genetics [Membrane Transport Proteins]; cytology [Monocytes]; Toll-Like Receptors; immunology [Adaptor Protein Complex 1]; Membrane Transport Proteins; immunology [B-Lymphocytes]; cytology [B-Lymphocytes]; immunology [Protein Transport]; Protein Transport; HEK293 Cells; immunology [Toll-Like Receptors]; genetics [Protein Transport]

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.