The Chaperone UNC93B1 Regulates Toll-like Receptor Stability Independently of Endosomal TLR Transport

Abstract

Unc-93 homolog B1 (UNC93B1) is a key regulator of nucleic acid (NA)-sensing Toll-like receptors (TLRs). Loss of NA-sensing TLR responses in UNC93B1-deficient patients facilitates Herpes simplex virus type 1 (HSV-1) encephalitis. UNC93B1 is thought to guide NA-sensing TLRs from the endoplasmic reticulum (ER) to their respective endosomal signaling compartments and to guide the flagellin receptor TLR5 to the cell surface, raising the question of how UNC93B1 mediates differential TLR trafficking. Here, we report that UNC93B1 regulates a step upstream of the differential TLR trafficking process. We discovered that UNC93B1 deficiency resulted in near-complete loss of TLR3 and TLR7 proteins in primary splenic mouse dendritic cells and macrophages, showing that UNC93B1 is critical for maintaining TLR expression. Notably, expression of an ER-retained UNC93B1 version was sufficient to stabilize TLRs and largely restore endosomal TLR trafficking and activity. These data are critical for an understanding of how UNC93B1 can regulate the function of a broad subset of TLRs.

Mapping Viral Susceptibility Loci in Mice

“…Using a positional cloning approach, researchers linked this poor response to TLR ligands to a missense allele of Unc93b1. Unc93b1 encodes the 12-membrane-spanning protein UNC93B1, a highly conserved molecule found in the endoplasmic reticulum, which plays an important role in the stability and intracellular trafficking of various TLR molecules (22)(23)(24). Importantly, Unc93b1-deficient mice have impaired clearance of MCMV (25), while UNC93B1-deficient human patients are prone to developing herpes simplex virus type 1 encephalitis (26).…”

RNA is taking its Toll: Impact of RNA‐specific Toll‐like receptors on health and disease

“…UNC93B1 interacts with the transmembrane domain of endosomal TLRs and was thought to direct them from the endoplasmatic reticulum (ER) through the Golgi apparatus to the endosomes and remains associated with the receptors until the target location is reached . However, this model of UNC93B1 is challenged by a recent study from the group of Eike Latz showing that UNC93B1 acts upstream of the trafficking process . NA‐sensing TLRs are still functional in cells expressing a modified version of UNC93B1 with ER‐retention motifs.…”

“…NA‐sensing TLRs are still functional in cells expressing a modified version of UNC93B1 with ER‐retention motifs. The authors demonstrate that UNC93B1 is not required to guide the receptors from the Golgi to the endosomes but that it is rather necessary to stabilize the TLRs in the ER and to protect them from degradation …”

Avian Pattern Recognition Receptor Sensing and Signaling

“…Furthermore, ligand responsiveness of chTLR21 in HD11 macrophages is sensitive to chloroquine treatment pointing to ER and endolysosomal functions. In human and mouse, UNC93B1 was demonstrated to control the stability and endosomal localization of TLR3, TLR7, and TLR9 [85]. Although human and mouse lack TLR21, zebra fish genomes contain an ortholog of mammalian TLR9, as well as fish-specific TLRs including TLR21, whose localization and activation was found to be regulated by UNC93B1 [85].…”