1. Trim-Away ubiquitinates and degrades lysine-less and N-terminally acetylated substrates
- Author
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Kiss, Leo, Rhinesmith, Tyler, Luptak, Jakub, Dickson, Claire F, Weidenhausen, Jonas, Smyly, Shannon, Yang, Ji-Chun, Maslen, Sarah L, Sinning, Irmgard, Neuhaus, David, Clift, Dean, James, Leo C, Kiss, Leo [0000-0001-8735-1118], Rhinesmith, Tyler [0000-0002-9983-0287], Luptak, Jakub [0000-0002-9527-8755], Dickson, Claire F [0000-0002-1972-4143], Weidenhausen, Jonas [0000-0001-8376-2083], Sinning, Irmgard [0000-0001-9127-4477], Neuhaus, David [0000-0002-8561-7485], Clift, Dean [0000-0001-8141-7817], James, Leo C [0000-0003-2131-0334], and Apollo - University of Cambridge Repository
- Subjects
Mammals ,Multidisciplinary ,Lysine ,Ubiquitin-Protein Ligases ,Proteolysis ,Ubiquitination ,General Physics and Astronomy ,Animals ,General Chemistry ,Protein Processing, Post-Translational ,General Biochemistry, Genetics and Molecular Biology - Abstract
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: https://doi.org/10.13039/501100001645, 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.
- Published
- 2023