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The Deubiquitinase TRABID Stabilises the K29/K48-Specific E3 Ubiquitin Ligase HECTD1', Journal of Biological Chemistry, Vol

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The Deubiquitinase TRABID Stabilises the K29/K48-Specific E3 Ubiquitin Ligase HECTD1', Journal of Biological Chemistry, Vol Citation for published version: Harris, LD, Le Pen, J, Scholz, N, Mieszczanek, J, Vaughan, N, Davis, S, Berridge, G, Kessler, B, Bienz, M & Licchesi, J 2021, 'The deubiquitinase TRABID stabilises the K29/K48-specific E3 ubiquitin ligase HECTD1', Journal of Biological Chemistry, vol. 296, no. 1, 100246. https://doi.org/10.1074/jbc.RA120.015162 DOI: 10.1074/jbc.RA120.015162 Publication date: 2021 Document Version Peer reviewed version Link to publication Publisher Rights Unspecified Copyright The Authors 2020. Harris, LD, Le Pen, J, Scholz, N, Mieszczanek, J, Vaughan, N, Davis, S, Berridge, G, Kessler, B, Bienz, M & Licchesi, J 2020, 'The deubiquitinase TRABID stabilises the K29/K48-specific E3 ubiquitin ligase HECTD1', Journal of Biological Chemistry. https://doi.org/10.1074/jbc.RA120.015162 University of Bath Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 09. Oct. 2021 JBC Papers in Press. Published on December 30, 2020 as Manuscript RA120.015162 The latest version is at https://www.jbc.org/cgi/doi/10.1074/jbc.RA120.015162 The deubiquitinase TRABID stabilises the K29/K48-specific E3 ubiquitin ligase HECTD1 Lee D. Harris1, 4, Janic Le Pen2, 4, Nico Scholz1, Juliusz Mieszczanek2, Natalie Vaughan1, Simon Davis3, Georgina Berridge3, Benedikt Kessler3, Mariann Bienz2 and Julien D. F. Licchesi1, * 1 Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom 2 MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, United Kingdom 3 Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, United Kingdom 4 These authors contributed equally * Correspondence to Julien D. F. Licchesi, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK. +44(0)1225 386 287; [email protected] Downloaded from Running title: Lys29-specific DUB-E3 pair Keywords: Ubiquitin, Deubiquitination, Polyubiquitin chain, E3 ubiquitin ligase, ubiquitin http://www.jbc.org/ thioesterase, Protein degradation, HECTD1, TRABID, K29/K48-linked polyubiquitin chain at University of Bath on December 30, 2020 1 distinct signals mediate specific and diverse Abstract downstream cellular processes. For example, Ubiquitin is a versatile post-translational while addition of a single ubiquitin molecule on modification which is covalently attached to a protein substrate can regulate its trafficking, protein targets either as a single moiety or as polyubiquitination regulates a plethora of a ubiquitin chain. In contrast to K48 and K63- cellular processes including cell cycle linked chains which have been extensively progression, DNA repair and inflammation (6- studied, the regulation and function of most 9). Polyubiquitin chains are assembled atypical ubiquitin chains is only starting to through an isopeptide bond between the C- emerge. The deubiquitinase terminus of Gly76 of a donor ubiquitin and the TRABID/ZRANB1 is tuned for the recognition and cleavage of K29 and K33-linked chains. a-amino group of any of the seven lysines (K6, Yet, substrates of TRABID and the cellular K11, K27, K29, K33, K48 and K63) or the N- functions of these atypical ubiquitin signals terminus (i.e., linear ubiquitin, Met-1) of an remain unclear. We determined the acceptor ubiquitin. Protein ubiquitination also interactome of two TRABID constructs occurs on non-canonical attachment sites rendered catalytic dead either through a point within substrates, including on serine, mutation in the catalytic cysteine residue or threonine, and cysteine residues (10-12). through removal of the OTU catalytic domain. Some deubiquitinases (DUB), in particular Downloaded from We identified 50 proteins trapped by both those from the Ovarian Tumour (OTU) family, constructs and which therefore represent and E3 ubiquitin ligases such as members of candidate substrates of TRABID. We then the Homologous to the E6AP carboxyl validated the E3 ubiquitin ligase HECTD1 as a terminus (HECT) family have shown substrate of TRABID and used UbiCREST specificity for particular ubiquitin chains. This, http://www.jbc.org/ and Ub-AQUA proteomics to show that combined with the difference in the three- HECTD1 preferentially assembles K29- and dimensional structure of these ubiquitin K48-linked ubiquitin chains. Further in vitro polymers, further suggests that they represent autoubiquitination assays using ubiquitin distinct signals (13). All ubiquitin linkage types mutants established that while HECTD1 can have been identified in yeast (14) and at University of Bath on December 30, 2020 assemble short homotypic K29 and K48- mammalian cells (15). While homotypic K48- linked chains, it requires branching at K29/K48 linked polyubiquitin chains target proteins for in order to achieve its full ubiquitin ligase degradation by the UPS, cargoes modified activity. We next used transient knockdown with K63-linked chains are recognised as part and genetic knock out of TRABID in of the autophagic response (16-18). mammalian cells in order to determine the Nevertheless, the role and function of functional relationship between TRABID and polyubiquitin chains beyond those assembled HECTD1. This revealed that upon TRABID through homotypic (i.e., assembled through depletion, HECTD1 is readily degraded. Thus, one lysine only) such as K48 and K63 this study identifies HECTD1 as a mammalian linkages, is only starting to emerge (19-21). E3 ligase which assembles branched K29/K48 More recently, polyubiquitin has been found to chains and also establishes TRABID-HECTD1 exist as heterotypic and also branched chains. as a DUB/E3 pair regulating K29 linkages. For example, branched K11/K48-linked chains Introduction increase the degradation rate of mitotic cyclins by the UPS, while branched K48/K63 chains Ubiquitin is a small and highly conserved regulate NF-kB gene activation through protein modifier which has emerged as a recognition by TAB2, a subunit of the TAK1 complex yet specific post-translational complex (22,23). modification regulating protein fate and TRABID (also known as ZRANB1), belongs to function. The role of ubiquitin is central to OTU DUB family (24). It contains three highly proteostasis by serving as the key signal for conserved Npl14 zinc finger domains (3xNZF) the degradation of proteins or organelles which function as ubiquitin binding domains whether it be through the Ubiquitin (UBD), and the OTU catalytic domain Proteasome System (UPS) or autophagy (1- responsible for the hydrolysis of ubiquitin 3). Ubiquitin is added to lysine residues on polymers (24-26). The expansion of the protein targets through the sequential activity ubiquitin toolbox through for example the of E1-activating enzymes, E2-conjugating chemical synthesis of ubiquitin dimers, has enzymes and E3 ubiquitin ligases, as a single been instrumental in determining TRABID’s moiety or as a ubiquitin chain (4,5). These specificity for K29-linked ubiquitin chains (27). 2 Further analysis using the full set of eight to further expand on our understanding of ubiquitin dimers revealed that in addition to TRABID as well as the atypical ubiquitin K29-linked ubiquitin dimers, TRABID also chains which it regulates. We first used two cleaves K33-linked ubiquitin chains and that catalytic dead TRABID constructs, a single the activity towards K29 and K33-linked point mutation in the catalytic OTU domain dimers is greater than for K63-linked (TRABIDC443S) and a construct lacking the diubiquitin (28). The discovery of the AnkUBD OTU domain entirely (TRABID DOTU), to as a novel UBD abutting the N-terminus of specifically trap ubiquitinated substrates. By TRABID OTU domain, revealed that it is comparing the interactome of these two required for full DUB activity, and to some constructs, we identified NZF- and OTU- extent specificity too. These findings as well as specific TRABID interactors, including several recent studies which identified TRABID’s NZF E3 ubiquitin ligases as candidate interactors 1 as the minimal UBD required for the and potential substrates of TRABID DUB recognition of K29- and K33-linked diubiquitin activity. We validated HECTD1 as a substrate establish TRABID as a unique DUB highly of TRABID activity and used in vitro tuned for the recognition and processing of autoubiquitination assays, Ubiquitin Chain these atypical ubiquitin chains (29-31). Restriction Analysis (UbiCREST) and Ubiquitin-Absolute QUAntification (Ub-AQUA) TRABID has been proposed to regulate the Downloaded from Wnt/b-catenin/Tcf signaling pathway through to show that the catalytic HECT domain of APC (Adenomatous Polyposis Coli), the HECTD1 preferentially assembles K29- and epithelial to mesenchymal transition (EMT) K48-linked ubiquitin chains. Interestingly, our through Twist, as well as the innate immune data indicate that although UBE3C and response, with these studies implicating the HECTD1 both use K29 and K48 linkages to http://www.jbc.org/ deubiquitination
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