Trim-Away ubiquitinates and degrades lysine-less and N-terminally acetylated substrates.

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TRIM proteins are the largest family of E3 ligases in mammals. They include the intracellular antibody receptor TRIM21, which is responsible for mediating targeted protein degradation during Trim-Away. Despite their importance, the ubiquitination mechanism of TRIM ligases has remained elusive. Here we show that while Trim-Away activation results in ubiquitination of both ligase and substrate, ligase ubiquitination is not required for substrate degradation. N-terminal TRIM21 RING ubiquitination by the E2 Ube2W can be inhibited by N-terminal acetylation, but this doesn't prevent substrate ubiquitination nor degradation. Instead, uncoupling ligase and substrate degradation prevents ligase recycling and extends functional persistence in cells. Further, Trim-Away degrades substrates irrespective of whether they contain lysines or are N-terminally acetylated, which may explain the ability of TRIM21 to counteract fast-evolving pathogens and degrade diverse substrates.


Acknowledgements: L.K. was supported by a Ph.D. Fellowship from the Boehringer Ingelheim Fonds. This work was supported by the MRC (UK; U105181010), a Wellcome Trust Investigator Award (223054/Z/21/Z) and a Wellcome Trust Collaborator Award (214344/A/18/Z).

Funder: Boehringer Ingelheim Fonds (Stiftung für medizinische Grundlagenforschung); doi:

Animals, Lysine, Ubiquitination, Ubiquitin-Protein Ligases, Protein Processing, Post-Translational, Proteolysis, Mammals
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Nat Commun
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Springer Science and Business Media LLC
Wellcome Trust (Wellcome) (223054/Z/21/Z, 214344/A/18/Z)