UNC93A

UNC93A is an endoplasmic reticulum (ER)-resident transmembrane protein that plays a critical role in innate immune signaling, particularly in the recognition of nucleic acids derived from pathogens. Specifically, UNC93A regulates the trafficking and localization of Toll-like receptors (TLRs) 3, 7, 9, and 13 (in mice), which are intracellular receptors involved in the detection of single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), and DNA.

UNC93A interacts directly with these TLRs, preventing them from prematurely signaling in the ER. This chaperone function is crucial for ensuring that TLR activation only occurs in the endolysosome, a cellular compartment containing proteases that are necessary to process and activate the receptors after they encounter their cognate ligands. By chaperoning these TLRs, UNC93A ensures appropriate receptor folding, stability, and trafficking to the endolysosome.

Mutations or polymorphisms in the UNC93A gene can lead to aberrant TLR signaling, resulting in increased susceptibility to inflammatory diseases, autoimmune disorders, and/or viral infections. Gain-of-function mutations can cause enhanced TLR responses, contributing to inflammation. Conversely, loss-of-function mutations may impair TLR signaling, rendering individuals more vulnerable to intracellular pathogens.

The precise mechanism by which UNC93A regulates TLR trafficking is still under investigation, but it is believed to involve interactions with other ER-resident proteins and the COPII machinery, which is responsible for ER-to-Golgi transport. Further research is necessary to fully elucidate the complex molecular mechanisms underlying UNC93A's role in TLR signaling and immune homeostasis.