S18-phosphorylation of USP7 regulates interaction with TCEAL4 that defines specific complexes and potentially distinct functions



Querques, Francesca, Darling, Sarah, Cheetham-Wilkinson, Izaak, Kim, Robbert Q, Hapangama, Dharani K, Sixma, Titia K ORCID: 0000-0001-6180-0632 and Coulson, Judy M
S18-phosphorylation of USP7 regulates interaction with TCEAL4 that defines specific complexes and potentially distinct functions.

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Abstract

<jats:title>Abstract</jats:title><jats:p>USP7 is a nuclear deubiquitylase (DUB) with multiple cancer-associated substrates for which selective inhibitors are available, yet it remains unclear how the pleiotropic effects of USP7 are regulated. We report that S18-phosphorylation does not influence USP7 catalytic activity but instead confers selectivity for protein interactions. In particular, non-S18-phosphorylatable USP7 preferentially interacts with USP11 and TRIM27, together with TCEAL1 and TCEAL4 whose functions are unknown. Intriguingly, USP7 can interact with two cellular forms of TCEAL4, but USP11 only interacts with a lower abundance K142 mono-ubiquitylated form (TCEAL4-Ub), which can scaffold a complex containing both DUBs. Whilst USP11 and TCEAL4 are both USP7 substrates, TCEAL4-Ub levels are specifically maintained by USP11 with their levels positively correlated in cancer cell lines. Together these data illustrate how USP7 phosphorylation and TCEAL4 ubiquitylation combine to define distinct USP7 complexes. As TCEAL4 itself interacts with proteins involved in ubiquitylation and various forms of DNA regulation, these complexes may direct cellular activity of USP7.</jats:p>

Item Type: Article
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 31 Aug 2021 08:19
Last Modified: 01 May 2022 11:32
DOI: 10.1101/2021.07.07.451439
URI: https://livrepository.liverpool.ac.uk/id/eprint/3135291