Ubiquitination of TLR3 by TRIM3 signals its ESCRT-mediated trafficking to the endolysosomes for innate antiviral response
| Autor: | Zhi-Sheng Xu, Su-Yun Wang, Mei-Guang Xiong, Wei-Wei Li, Yan Yang, Yong Ran, Ying Nie, Yan-Yi Wang, Wei-Wei Luo |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Endosome viruses chemical and pharmacologic phenomena Antiviral Agents ESCRT 03 medical and health sciences symbols.namesake Mice 0302 clinical medicine Ubiquitin Animals Humans Multidisciplinary Innate immune system biology Endosomal Sorting Complexes Required for Transport Chemistry Endoplasmic reticulum Ubiquitination Golgi apparatus Biological Sciences Immunity Innate Cell biology Ubiquitin ligase Toll-Like Receptor 3 Protein Transport 030104 developmental biology HEK293 Cells TLR3 biology.protein symbols RNA Viral Carrier Proteins Lysosomes 030215 immunology Signal Transduction |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 |
| Popis: | Trafficking of toll-like receptor 3 (TLR3) from the endoplasmic reticulum (ER) to endolysosomes and its subsequent proteolytic cleavage are required for it to sense viral double-stranded RNA (dsRNA) and trigger antiviral response, yet the underlying mechanisms remain enigmatic. We show that the E3 ubiquitin ligase TRIM3 is mainly located in the Golgi apparatus and transported to the early endosomes upon stimulation with the dsRNA analog poly(I:C). TRIM3 mediates K63-linked polyubiquitination of TLR3 at K831, which is enhanced following poly(I:C) stimulation. The polyubiquitinated TLR3 is recognized and sorted by the ESCRT (endosomal sorting complex required for transport) complexes to endolysosomes. Deficiency of TRIM3 impairs TLR3 trafficking from the Golgi apparatus to endosomes and its subsequent activation. Trim3(−/−) cells and mice express lower levels of antiviral genes and show lower levels of inflammatory response following poly(I:C) but not lipopolysaccharide (LPS) stimulation. These findings suggest that TRIM3-mediated polyubiquitination of TLR3 represents a feedback-positive regulatory mechanism for TLR3-mediated innate immune and inflammatory responses. |
| Databáze: | OpenAIRE |
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