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The antibody receptor and ubiquitin ligase TRIM21 recognizes antibody-bound pathogens and triggers their proteasomal degradation. Using TRIM21, Clift et al. developed a new post-translational protein knockdown approach called Trim-Away in which an antibody specific for the protein of interest is introduced into mammalian cells either through microinjection or electroporation, leading to TRIM21-mediated specific and rapid degradation of the target protein within minutes. In some cell lines, endogenous TRIM21 levels are sufficient to achieve degradation; alternatively, TRIM21 can be heterologously expressed in cells, or purified TRIM21 can be inserted together with the antibody by electroporation. Both cytosolic and membrane-anchored proteins can be targeted by Trim-Away in this manner, and nuclear proteins can also be selectively degraded by using a nanobody fused to the Fc domain of an antibody, which is required for TRIM21 recognition. The authors demonstrate the promise of this method by showing that specific variants of a protein, for example a disease-causing form of huntingtin, can be selectively degraded, as can long-lived proteins and proteins in primary cells, for which RNAi experiments are challenging. Trim-Away will open up new avenues for research because it is an easily applicable tool for studying protein function that can be used for most intracellular proteins.
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Kuehnel, K. Eaten up from the inside. Nat Chem Biol 14, 107 (2018). https://doi.org/10.1038/nchembio.2563
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DOI: https://doi.org/10.1038/nchembio.2563