Ubiquitination of TLR3 by TRIM3 signals its ESCRT-mediated trafficking to the endolysosomes for innate antiviral response

Significance Trafficking of TLR3 from the ER to endolysosomes and its subsequent proteolytic cleavage are necessary for it to sense viral dsRNA and trigger antiviral response. Understanding how TLR3 trafficking is regulated is important for deciphering the mechanism of TLR3-mediated innate immune and inflammatory responses. In this study, we report that TRIM3 mediates K63-linked polyubiquitination of TLR3 at K831. Subsequently, the polyubiquitinated TLR3 is recognized and sorted by the ESCRT complexes to endolysosomes to promote the activation of downstream signaling. This study provides insights into how the trafficking and activation of TLR3 are regulated for efficient innate immune response to extracellular and endosomal viral dsRNA.