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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\n                    <jats:italic>Drosophila<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41467-023-42342-y","type":"journal-article","created":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T06:02:58Z","timestamp":1698386578000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity"],"prefix":"10.1038","volume":"14","author":[{"given":"Sylvia","family":"Varland","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2168-8599","authenticated-orcid":false,"given":"Rui Duarte","family":"Silva","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0619-9658","authenticated-orcid":false,"given":"Ine","family":"Kjos\u00e5s","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9175-5561","authenticated-orcid":false,"given":"Alexandra","family":"Faustino","sequence":"additional","affiliation":[]},{"given":"Annelies","family":"Bogaert","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6556-9594","authenticated-orcid":false,"given":"Maximilian","family":"Billmann","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0330-3344","authenticated-orcid":false,"given":"Hadi","family":"Boukhatmi","sequence":"additional","affiliation":[]},{"given":"Barbara","family":"Kellen","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7906-2604","authenticated-orcid":false,"given":"Michael","family":"Costanzo","sequence":"additional","affiliation":[]},{"given":"Adrian","family":"Drazic","sequence":"additional","affiliation":[]},{"given":"Camilla","family":"Osberg","sequence":"additional","affiliation":[]},{"given":"Katherine","family":"Chan","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5916-1357","authenticated-orcid":false,"given":"Xiang","family":"Zhang","sequence":"additional","affiliation":[]},{"given":"Amy Hin Yan","family":"Tong","sequence":"additional","affiliation":[]},{"given":"Simonetta","family":"Andreazza","sequence":"additional","affiliation":[]},{"given":"Juliette J.","family":"Lee","sequence":"additional","affiliation":[]},{"given":"Lyudmila","family":"Nedyalkova","sequence":"additional","affiliation":[]},{"given":"Matej","family":"U\u0161aj","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1154-6629","authenticated-orcid":false,"given":"Alexander J.","family":"Whitworth","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6427-6493","authenticated-orcid":false,"given":"Brenda J.","family":"Andrews","sequence":"additional","affiliation":[]},{"given":"Jason","family":"Moffat","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1026-5972","authenticated-orcid":false,"given":"Chad L.","family":"Myers","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4237-0283","authenticated-orcid":false,"given":"Kris","family":"Gevaert","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3542-6760","authenticated-orcid":false,"given":"Charles","family":"Boone","sequence":"additional","affiliation":[]},{"given":"Rui Gon\u00e7alo","family":"Martinho","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3005-147X","authenticated-orcid":false,"given":"Thomas","family":"Arnesen","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,10,27]]},"reference":[{"key":"42342_CR1","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1002\/pmic.201400619","volume":"15","author":"S Varland","year":"2015","unstructured":"Varland, S., Osberg, C. & Arnesen, T. 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