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 ER to endolysosomes, where the TLRs encounter their respective ligands and become activated. Here we show that a carboxy-terminal tyrosine-based sorting motif (Yxx Φ) in UNC93B1 differentially regulates human nucleic acid sensing TLRs in a receptor- and ligand-specific manner. Destruction of the YxxΦ motif abolished TLR7, 8 and 9 activity towards nucleic acids in human B cells and monocytes, whereas TLR8 responses towards small molecules remained intact. The YxxΦ motif in UNC93B1 influenced the subcellular localization of human UNC93B1 via both adapter protein complex 1 (AP1)- and AP2-dependent trafficking pathways. However, loss of AP function was not causal for altered TLR responses, suggesting AP-independent functions of the YxxΦ motif in UNC93B1.

CD11c+ T-bet+ memory B cells: Immune maintenance during chronic infection and inflammation?

“…Moreover, our studies of MyD88 mice failed to reveal any change in the generation of CD11c+ T-bet+ plasmablasts in the absence of MyD88-dependent TLR signaling (unpublished data). We performed additional studies to address whether TLR signaling played any role in the generation of CD11c+ T-bet+ IgM memory cell, by utilizing Unc93b-deficient mice, which are deficient in TLR3, 7, 8, and 9 signaling [60, 61]. Generation of the CD11c+ T-bet+ IgM memory B cells was unaffected by the absence of Unc93b (Figure 2).…”

Compartmentalizing intestinal epithelial cell toll-like receptors for immune surveillance

“…Although UNC93B1 contains a C-terminus localized YXXØ motif that mediates AP1- and AP2-dependent UNC93B1 traffic, it does not contain any domain that may power the trafficking of TLR/UNC93B1 on actin or microtubule filaments. Disruption of this YXXØ motif leads to different effects of endosomal TLR signaling that is dependent on the cell types and the ligands [114]. Identification of additional trafficking components, such as the motors and the specific small GTPases that engage in UNC93B1-mediated TLR transport will elucidate additional mechanisms of endosomal TLR compartmentalization and signaling.…”

TLR8 Senses Bacterial RNA in Human Monocytes and Plays a Nonredundant Role for Recognition of Streptococcus pyogenes

“…Human UNC93B1-knockout THP-1 monocytes generated by CRISPR/ Cas9-based gene editing were retrovirally transduced with UNC93B1-mCitrine WT or nonfunctional H412R mutant and have been described previously (24,25). THP-1 cells were differentiated overnight with 100 nM PMA in RPMI 1640 supplemented with 10% FCS prior to stimulation.…”