HERC2 deficiency activates C-RAF/MKK3/p38 signalling pathway altering the cellular response to oxidative stress

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dc.citation.issue11
dc.citation.spage548
dc.citation.volume79
dc.contributor.authorSala-Gaston, J.
dc.contributor.authorPedrazza, L.
dc.contributor.authorRamirez, J.
dc.contributor.authorMartinez-Martinez, A.
dc.contributor.authorRawlins, L. E.
dc.contributor.authorBaple, E. L.
dc.contributor.authorCrosby, A. H.
dc.contributor.authorMayor, U.
dc.contributor.authorVentura, F.
dc.contributor.authorRosa, J. L.
dc.date.accessioned2023-01-12T14:24:40Z
dc.date.available2023-01-12T14:24:40Z
dc.date.epub2022-10-15
dc.date.issued2022-10-14
dc.description.abstractHERC2 gene encodes an E3 ubiquitin ligase involved in several cellular processes by regulating the ubiquitylation of different protein substrates. Biallelic pathogenic sequence variants in the HERC2 gene are associated with HERC2 Angelman-like syndrome. In pathogenic HERC2 variants, complete absence or marked reduction in HERC2 protein levels are observed. The most common pathological variant, c.1781C > T (p.Pro594Leu), encodes an unstable HERC2 protein. A better understanding of how pathologic HERC2 variants affect intracellular signalling may aid definition of potential new therapies for these disorders. For this purpose, we studied patient-derived cells with the HERC2 Pro594Leu variant. We observed alteration of mitogen-activated protein kinase signalling pathways, reflected by increased levels of C-RAF protein and p38 phosphorylation. HERC2 knockdown experiments reproduced the same effects in other human and mouse cells. Moreover, we demonstrated that HERC2 and RAF proteins form molecular complexes, pull-down and proteomic experiments showed that HERC2 regulates C-RAF ubiquitylation and we found out that the p38 activation due to HERC2 depletion occurs in a RAF/MKK3-dependent manner. The displayed cellular response was that patient-derived and other human cells with HERC2 deficiency showed higher resistance to oxidative stress with an increase in the master regulator of the antioxidant response NRF2 and its target genes. This resistance was independent of p53 and abolished by RAF or p38 inhibitors. Altogether, these findings identify the activation of C-RAF/MKK3/p38 signalling pathway in HERC2 Angelman-like syndrome and highlight the inhibition of RAF activity as a potential therapeutic option for individuals affected with these rare diseases.
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dc.identifier.citationCell Mol Life Sci. 2022 Oct 14;79(11):548. doi: 10.1007/s00018-022-04586-7.
dc.identifier.doi10.1007/s00018-022-04586-7
dc.identifier.journalCellular and molecular life sciences
dc.identifier.pmcidPMC9568463
dc.identifier.pmid36241744
dc.identifier.urihttps://hdl.handle.net/11287/622716
dc.language.isoeng
dc.publisherSpringer
dc.relation.urlhttps://doi.org/10.1007/s00018-022-04586-7
dc.rights© 2022. The Author(s).
dc.subjectAnimals
dc.subjectAntioxidants/metabolism
dc.subjectGuanine Nucleotide Exchange Factors/genetics/metabolism
dc.subjectHumans
dc.subjectMice
dc.subjectMitogen-Activated Protein Kinases/metabolism
dc.subjectNF-E2-Related Factor 2/genetics/metabolism
dc.subjectOxidative Stress
dc.subjectProtein Serine-Threonine Kinases
dc.subjectProteomics
dc.subjectProto-Oncogene Proteins/metabolism
dc.subject*Proto-Oncogene Proteins c-raf/metabolism
dc.subject*Tumor Suppressor Protein p53/metabolism
dc.subjectUbiquitin-Protein Ligases/genetics/metabolism
dc.subjectp38 Mitogen-Activated Protein Kinases/genetics/metabolism
dc.subjectAngelman
dc.subjectCell stress
dc.subjectMapk
dc.subjectNeurodevelopmental disorder
dc.subjectUbiquitin
dc.titleHERC2 deficiency activates C-RAF/MKK3/p38 signalling pathway altering the cellular response to oxidative stress
dc.typeJournal Article
dc.type.versionepublish
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