TRIM21 drives antibody-directed xenophagy of adenovirus and Salmonella in human cell lines and mice
Researchers described a pathway in which antibody-tagged pathogens are degraded inside the cell. In mice it reduced Salmonella pathology and tissue invasion.
A team from the Medical Research Council Laboratory of Molecular Biology has described a previously unknown antimicrobial pathway in mammalian cells. The authors call it antibody-directed xenophagy (ADX) and report it in Molecular Cell. According to the paper, the mechanism restricts structurally diverse pathogens, including adenovirus and Salmonella sciencedirect.com
Molecular Cellsciencedirect.comOpen source ↗. The work was done in human cell lines and in mice.
How the pathway works
TRIM21 is a ubiquitin ligase that antibodies can direct to oligomeric protein scaffolds, viral capsids and proteopathic aggregates for degradation inside the cell. How the cell degrades these typically resistant substrates was poorly understood. To address this, the authors used TRIM21 viral restriction to build a genome-wide phenotypic screen for antibody-dependent capsid degradation. According to the publisher's account, the team used CRISPR-Cas9.
Quantitative microscopy showed that TRIM21 rapidly intercepts antibody-pathogen complexes, which activates its ubiquitin ligase function. Selective autophagy adaptors are then recruited, and the viral cargo is delivered to lysosomes. TRIM21 marks the pathogen with ubiquitin, the signal that tells the cell it has been invaded.
Tests in cells and mice
The researchers checked the action of TRIM21 against adenovirus in a range of human cell lines. Salmonella was tested in live mice. In mice, ADX reduced Salmonella pathology and bacterial tissue invasion sciencedirect.com
Molecular Cellsciencedirect.comOpen source ↗. Co-author Tyler Rhinesmith said the data suggest that TRIM21 triggers ubiquitination of any pathogen surrounded by antibodies, and that this leads to autophagy of the bacterium or virus.
TRIM21 is encoded by an interferon-stimulated gene, so the body produces it in many tissues. Lead author Leo James said that without TRIM21 a significant part of protective immunity against viruses in vivo is lost. The authors propose that TRIM21 evolved through competition with pathogens to induce autophagy of diverse and complex substrates, which may explain its versatility in targeted protein degradation.
TRIM21 is the first intracellular protein found to stimulate ADX, and others may exist. The team's next steps are to look for other ADX-stimulating proteins and to determine the limits of TRIM21 function. The authors note that antibody-based or small-molecule agents might be used in the future to mark pathogens for TRIM21, but much more research is needed before any therapeutic option.
