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Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling

Cullin 3 (CUL3) is the scaffold of Cullin3 Ring E3-ligases (CRL3s), which use various BTB-adaptor proteins to ubiquitinate numerous substrates targeting their proteasomal degradation. CUL3 mutations, responsible for a severe form of familial hyperkalemia and hypertension (FHHt), all result in a dele...

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Autores principales: Kouranti, Ilektra, Abdel Khalek, Waed, Mazurkiewicz, Stephani, Loisel-Ferreira, Irmine, Gautreau, Alexis M., Pintard, Lionel, Jeunemaitre, Xavier, Clauser, Eric
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105235/
https://www.ncbi.nlm.nih.gov/pubmed/35563538
http://dx.doi.org/10.3390/ijms23095151
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author Kouranti, Ilektra
Abdel Khalek, Waed
Mazurkiewicz, Stephani
Loisel-Ferreira, Irmine
Gautreau, Alexis M.
Pintard, Lionel
Jeunemaitre, Xavier
Clauser, Eric
author_facet Kouranti, Ilektra
Abdel Khalek, Waed
Mazurkiewicz, Stephani
Loisel-Ferreira, Irmine
Gautreau, Alexis M.
Pintard, Lionel
Jeunemaitre, Xavier
Clauser, Eric
author_sort Kouranti, Ilektra
collection PubMed
description Cullin 3 (CUL3) is the scaffold of Cullin3 Ring E3-ligases (CRL3s), which use various BTB-adaptor proteins to ubiquitinate numerous substrates targeting their proteasomal degradation. CUL3 mutations, responsible for a severe form of familial hyperkalemia and hypertension (FHHt), all result in a deletion of exon 9 (amino-acids 403-459) (CUL3-∆9). Surprisingly, while CUL3-∆9 is hyperneddylated, a post-translational modification that typically activates CRL complexes, it is unable to ubiquitinate its substrates. In order to understand the mechanisms behind this loss-of function, we performed comparative label-free quantitative analyses of CUL3 and CUL3-∆9 interactome by mass spectrometry. It was observed that CUL3-∆9 interactions with COP9 and CAND1, both involved in CRL3 complexes’ dynamic assembly, were disrupted. These defects result in a reduction in the dynamic cycling of the CRL3 complexes, making the CRL3-∆9 complex an inactive BTB-adaptor trap, as demonstrated by SILAC experiments. Collectively, the data indicated that the hyperneddylated CUL3-∆9 protein is inactive as a consequence of several structural changes disrupting its dynamic interactions with key regulatory partners.
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spelling pubmed-91052352022-05-14 Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling Kouranti, Ilektra Abdel Khalek, Waed Mazurkiewicz, Stephani Loisel-Ferreira, Irmine Gautreau, Alexis M. Pintard, Lionel Jeunemaitre, Xavier Clauser, Eric Int J Mol Sci Article Cullin 3 (CUL3) is the scaffold of Cullin3 Ring E3-ligases (CRL3s), which use various BTB-adaptor proteins to ubiquitinate numerous substrates targeting their proteasomal degradation. CUL3 mutations, responsible for a severe form of familial hyperkalemia and hypertension (FHHt), all result in a deletion of exon 9 (amino-acids 403-459) (CUL3-∆9). Surprisingly, while CUL3-∆9 is hyperneddylated, a post-translational modification that typically activates CRL complexes, it is unable to ubiquitinate its substrates. In order to understand the mechanisms behind this loss-of function, we performed comparative label-free quantitative analyses of CUL3 and CUL3-∆9 interactome by mass spectrometry. It was observed that CUL3-∆9 interactions with COP9 and CAND1, both involved in CRL3 complexes’ dynamic assembly, were disrupted. These defects result in a reduction in the dynamic cycling of the CRL3 complexes, making the CRL3-∆9 complex an inactive BTB-adaptor trap, as demonstrated by SILAC experiments. Collectively, the data indicated that the hyperneddylated CUL3-∆9 protein is inactive as a consequence of several structural changes disrupting its dynamic interactions with key regulatory partners. MDPI 2022-05-05 /pmc/articles/PMC9105235/ /pubmed/35563538 http://dx.doi.org/10.3390/ijms23095151 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kouranti, Ilektra
Abdel Khalek, Waed
Mazurkiewicz, Stephani
Loisel-Ferreira, Irmine
Gautreau, Alexis M.
Pintard, Lionel
Jeunemaitre, Xavier
Clauser, Eric
Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling
title Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling
title_full Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling
title_fullStr Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling
title_full_unstemmed Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling
title_short Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling
title_sort cullin 3 exon 9 deletion in familial hyperkalemic hypertension impairs cullin3-ring-e3 ligase (crl3) dynamic regulation and cycling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105235/
https://www.ncbi.nlm.nih.gov/pubmed/35563538
http://dx.doi.org/10.3390/ijms23095151
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