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N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity

2023-10Journal article Open access
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dc.contributor.authorVarland, Sylvia
dc.contributor.authorSilva, Rui Duarte
dc.contributor.authorKjosås, Ine
dc.contributor.authorFaustino, Alexandra
dc.contributor.authorBogaert, Annelies
dc.contributor.authorBillmann, Maximilian
dc.contributor.authorBoukhatmi, Hadi
dc.contributor.authorKellen, Barbara
dc.contributor.authorCostanzo, Michael
dc.contributor.authorDrazic, Adrian
dc.contributor.authorOsberg, Camilla
dc.contributor.authorChan, Katherine
dc.contributor.authorZhang, Xiang
dc.contributor.authorTong, Amy Hin Yan
dc.contributor.authorAndreazza, Simonetta
dc.contributor.authorLee, Juliette J.
dc.contributor.authorNedyalkova, Lyudmila
dc.contributor.authorUšaj, Matej
dc.contributor.authorWhitworth, Alexander J.
dc.contributor.authorAndrews, Brenda J.
dc.contributor.authorMoffat, Jason
dc.contributor.authorMyers, Chad L.
dc.contributor.authorGevaert, Kris
dc.contributor.authorBoone, Charles
dc.contributor.authorMartinho, Rui Gonçalo
dc.contributor.authorArnesen, Thomas
dc.date.accessioned2024-01-04T11:38:49Z
dc.date.available2024-01-04T11:38:49Z
dc.date.issued2023-10
dc.description.abstractMost eukaryotic proteins are N-terminally acetylated, but the functional impact on a global scale has remained obscure. Using genome-wide CRISPR knockout screens in human cells, we reveal a strong genetic dependency between a major N-terminal acetyltransferase and specific ubiquitin ligases. Biochemical analyses uncover that both the ubiquitin ligase complex UBR4-KCMF1 and the acetyltransferase NatC recognize proteins bearing an unacetylated N-terminal methionine followed by a hydrophobic residue. NatC KO-induced protein degradation and phenotypes are reversed by UBR knockdown, demonstrating the central cellular role of this interplay. We reveal that loss of Drosophila NatC is associated with male sterility, reduced longevity, and age-dependent loss of motility due to developmental muscle defects. Remarkably, muscle-specific overexpression of UbcE2M, one of the proteins targeted for NatC KO-mediated degradation, suppresses defects of NatC deletion. In conclusion, NatC-mediated N-terminal acetylation acts as a protective mechanism against protein degradation, which is relevant for increased longevity and motility. The most common protein modification in eukaryotes is N-terminal acetylation, but its functional impact has remained enigmatic. Here, the authors find that a key role for N-terminal acetylation is shielding proteins from ubiquitin ligase-mediated degradation, mediating motility and longevity.pt_PT
dc.description.sponsorshipAssociation Francaise contre les Myopathies 261981, Canadian Institutes of Health Research (CIHR) 249843, United States Department of Health & Human Services National Institutes of Health (NIH) - USA F-12540, Portuguese national funding through Fundaco para a Ciencia e a Tecnologia (FCT) 171752-PR-2009-0222, National Funds through Fundaco para a Ciencia e a Tecnologia (FCT) G008018N, G002721N, University of Bergen MC_UU_00028/6, FDN-143264, FDN-143265, PJT-180285, PJT-463531, R01HG005853, R01HG005084, DL 57/2016/CP1361/CT0019, 2022.01782.PTDC,PTDC/BIA-BID/28441/2017,PTDC/BIA-BID/1606/2020, ALG-01-0145-FEDER-028441, PPBI-POCI-01-0145-FEDER-022122, LISBOA-01-0145-FEDER-022170pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1038/s41467-023-42342-ypt_PT
dc.identifier.eissn2041-1723
dc.identifier.urihttp://hdl.handle.net/10400.1/20267
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherNature Portfoliopt_PT
dc.relationEuropean Proteomics Infrastructure Consortium providing Access
dc.relationMarie Curie cofunding of the FRICON mobility programme in the Research Council of Norway scheme for independent basic research projects
dc.relationDiscovery and functional significance of post-translational N-terminal acetylation
dc.relationBiogenesis of Oncogenic MicroRNAs : from the structure of the microRNA processing complexes to the inhibition of the maturation of human oncogenes
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectArf-like gtpasept_PT
dc.subjectEnd rule pathwaypt_PT
dc.subjectCellular-proteinspt_PT
dc.subjectGene-expressionpt_PT
dc.subjectAlpha-acetyransferasept_PT
dc.subjectTranscription factorpt_PT
dc.subjectMuscle developmentpt_PT
dc.subjectE3 ligasept_PT
dc.subjectDrosophilapt_PT
dc.subjectComplexpt_PT
dc.titleN-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleEuropean Proteomics Infrastructure Consortium providing Access
oaire.awardTitleMarie Curie cofunding of the FRICON mobility programme in the Research Council of Norway scheme for independent basic research projects
oaire.awardTitleDiscovery and functional significance of post-translational N-terminal acetylation
oaire.awardTitleBiogenesis of Oncogenic MicroRNAs : from the structure of the microRNA processing complexes to the inhibition of the maturation of human oncogenes
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/823839/EU
oaire.awardURIinfo:eu-repo/grantAgreement/EC/FP7/608695/EU
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/772039/EU
oaire.awardURIinfo:eu-repo/grantAgreement/EC/FP7/231082/EU
oaire.citation.issue1pt_PT
oaire.citation.titleNature Communicationspt_PT
oaire.citation.volume14pt_PT
oaire.fundingStreamH2020
oaire.fundingStreamFP7
oaire.fundingStreamH2020
oaire.fundingStreamFP7
person.familyNameSilva
person.familyNameFaustino
person.familyNameViegas Russo da Conceição Martinho
person.givenNameRui
person.givenNameAlexandra
person.givenNameRui Gonçalo
person.identifier.ciencia-id051C-220E-D733
person.identifier.ciencia-idF31D-C783-3D89
person.identifier.orcid0000-0003-2168-8599
person.identifier.orcid0000-0001-9175-5561
person.identifier.orcid0000-0002-1641-3403
person.identifier.ridC-5622-2012
person.identifier.scopus-author-id15045741700
person.identifier.scopus-author-id6506186242
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
project.funder.nameEuropean Commission
project.funder.nameEuropean Commission
project.funder.nameEuropean Commission
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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