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

Leo Kiss (), Tyler Rhinesmith, Jakub Luptak, Claire F. Dickson, Jonas Weidenhausen, Shannon Smyly, Ji-Chun Yang, Sarah L. Maslen, Irmgard Sinning, David Neuhaus, Dean Clift () and Leo C. James ()
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Leo Kiss: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Tyler Rhinesmith: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Jakub Luptak: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Claire F. Dickson: EMBL Australia Node in Single Molecule Science and ARC Centre of Excellence in Advanced Molecular Imaging School of Medical Sciences
Jonas Weidenhausen: Biochemiezentrum der Universität Heidelberg (BZH), INF328
Shannon Smyly: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Ji-Chun Yang: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Sarah L. Maslen: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Irmgard Sinning: Biochemiezentrum der Universität Heidelberg (BZH), INF328
David Neuhaus: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Dean Clift: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Leo C. James: MRC Laboratory of Molecular Biology, Francis Crick Avenue

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37504-x

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