Cargando…
Regulation of canonical Wnt signalling by the ciliopathy protein MKS1 and the E2 ubiquitin-conjugating enzyme UBE2E1
Primary ciliary defects cause a group of developmental conditions known as ciliopathies. Here, we provide mechanistic insight into ciliary ubiquitin processing in cells and for mouse model lacking the ciliary protein Mks1. In vivo loss of Mks1 sensitises cells to proteasomal disruption, leading to a...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8880992/ https://www.ncbi.nlm.nih.gov/pubmed/35170427 http://dx.doi.org/10.7554/eLife.57593 |
_version_ | 1784659369761177600 |
---|---|
author | Szymanska, Katarzyna Boldt, Karsten Logan, Clare V Adams, Matthew Robinson, Philip A Ueffing, Marius Zeqiraj, Elton Wheway, Gabrielle Johnson, Colin A |
author_facet | Szymanska, Katarzyna Boldt, Karsten Logan, Clare V Adams, Matthew Robinson, Philip A Ueffing, Marius Zeqiraj, Elton Wheway, Gabrielle Johnson, Colin A |
author_sort | Szymanska, Katarzyna |
collection | PubMed |
description | Primary ciliary defects cause a group of developmental conditions known as ciliopathies. Here, we provide mechanistic insight into ciliary ubiquitin processing in cells and for mouse model lacking the ciliary protein Mks1. In vivo loss of Mks1 sensitises cells to proteasomal disruption, leading to abnormal accumulation of ubiquitinated proteins. We identified UBE2E1, an E2 ubiquitin-conjugating enzyme that polyubiquitinates β-catenin, and RNF34, an E3 ligase, as novel interactants of MKS1. UBE2E1 and MKS1 colocalised, and loss of UBE2E1 recapitulates the ciliary and Wnt signalling phenotypes observed during loss of MKS1. Levels of UBE2E1 and MKS1 are co-dependent and UBE2E1 mediates both regulatory and degradative ubiquitination of MKS1. We demonstrate that processing of phosphorylated β-catenin occurs at the ciliary base through the functional interaction between UBE2E1 and MKS1. These observations suggest that correct β-catenin levels are tightly regulated at the primary cilium by a ciliary-specific E2 (UBE2E1) and a regulatory substrate-adaptor (MKS1). |
format | Online Article Text |
id | pubmed-8880992 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-88809922022-02-26 Regulation of canonical Wnt signalling by the ciliopathy protein MKS1 and the E2 ubiquitin-conjugating enzyme UBE2E1 Szymanska, Katarzyna Boldt, Karsten Logan, Clare V Adams, Matthew Robinson, Philip A Ueffing, Marius Zeqiraj, Elton Wheway, Gabrielle Johnson, Colin A eLife Cell Biology Primary ciliary defects cause a group of developmental conditions known as ciliopathies. Here, we provide mechanistic insight into ciliary ubiquitin processing in cells and for mouse model lacking the ciliary protein Mks1. In vivo loss of Mks1 sensitises cells to proteasomal disruption, leading to abnormal accumulation of ubiquitinated proteins. We identified UBE2E1, an E2 ubiquitin-conjugating enzyme that polyubiquitinates β-catenin, and RNF34, an E3 ligase, as novel interactants of MKS1. UBE2E1 and MKS1 colocalised, and loss of UBE2E1 recapitulates the ciliary and Wnt signalling phenotypes observed during loss of MKS1. Levels of UBE2E1 and MKS1 are co-dependent and UBE2E1 mediates both regulatory and degradative ubiquitination of MKS1. We demonstrate that processing of phosphorylated β-catenin occurs at the ciliary base through the functional interaction between UBE2E1 and MKS1. These observations suggest that correct β-catenin levels are tightly regulated at the primary cilium by a ciliary-specific E2 (UBE2E1) and a regulatory substrate-adaptor (MKS1). eLife Sciences Publications, Ltd 2022-02-16 /pmc/articles/PMC8880992/ /pubmed/35170427 http://dx.doi.org/10.7554/eLife.57593 Text en © 2022, Szymanska et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Szymanska, Katarzyna Boldt, Karsten Logan, Clare V Adams, Matthew Robinson, Philip A Ueffing, Marius Zeqiraj, Elton Wheway, Gabrielle Johnson, Colin A Regulation of canonical Wnt signalling by the ciliopathy protein MKS1 and the E2 ubiquitin-conjugating enzyme UBE2E1 |
title | Regulation of canonical Wnt signalling by the ciliopathy protein MKS1 and the E2 ubiquitin-conjugating enzyme UBE2E1 |
title_full | Regulation of canonical Wnt signalling by the ciliopathy protein MKS1 and the E2 ubiquitin-conjugating enzyme UBE2E1 |
title_fullStr | Regulation of canonical Wnt signalling by the ciliopathy protein MKS1 and the E2 ubiquitin-conjugating enzyme UBE2E1 |
title_full_unstemmed | Regulation of canonical Wnt signalling by the ciliopathy protein MKS1 and the E2 ubiquitin-conjugating enzyme UBE2E1 |
title_short | Regulation of canonical Wnt signalling by the ciliopathy protein MKS1 and the E2 ubiquitin-conjugating enzyme UBE2E1 |
title_sort | regulation of canonical wnt signalling by the ciliopathy protein mks1 and the e2 ubiquitin-conjugating enzyme ube2e1 |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8880992/ https://www.ncbi.nlm.nih.gov/pubmed/35170427 http://dx.doi.org/10.7554/eLife.57593 |
work_keys_str_mv | AT szymanskakatarzyna regulationofcanonicalwntsignallingbytheciliopathyproteinmks1andthee2ubiquitinconjugatingenzymeube2e1 AT boldtkarsten regulationofcanonicalwntsignallingbytheciliopathyproteinmks1andthee2ubiquitinconjugatingenzymeube2e1 AT loganclarev regulationofcanonicalwntsignallingbytheciliopathyproteinmks1andthee2ubiquitinconjugatingenzymeube2e1 AT adamsmatthew regulationofcanonicalwntsignallingbytheciliopathyproteinmks1andthee2ubiquitinconjugatingenzymeube2e1 AT robinsonphilipa regulationofcanonicalwntsignallingbytheciliopathyproteinmks1andthee2ubiquitinconjugatingenzymeube2e1 AT ueffingmarius regulationofcanonicalwntsignallingbytheciliopathyproteinmks1andthee2ubiquitinconjugatingenzymeube2e1 AT zeqirajelton regulationofcanonicalwntsignallingbytheciliopathyproteinmks1andthee2ubiquitinconjugatingenzymeube2e1 AT whewaygabrielle regulationofcanonicalwntsignallingbytheciliopathyproteinmks1andthee2ubiquitinconjugatingenzymeube2e1 AT johnsoncolina regulationofcanonicalwntsignallingbytheciliopathyproteinmks1andthee2ubiquitinconjugatingenzymeube2e1 |