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

Sylvia Varland (), Rui Duarte Silva (), Ine Kjosås, Alexandra Faustino, Annelies Bogaert, Maximilian Billmann, Hadi Boukhatmi, Barbara Kellen, Michael Costanzo, Adrian Drazic, Camilla Osberg, Katherine Chan, Xiang Zhang, Amy Hin Yan Tong, Simonetta Andreazza, Juliette J. Lee, Lyudmila Nedyalkova, Matej Ušaj, Alexander J. Whitworth, Brenda J. Andrews, Jason Moffat, Chad L. Myers, Kris Gevaert, Charles Boone, Rui Gonçalo Martinho () and Thomas Arnesen ()
Additional contact information
Sylvia Varland: University of Bergen
Rui Duarte Silva: Universidade do Algarve
Ine Kjosås: University of Bergen
Alexandra Faustino: Universidade do Algarve
Annelies Bogaert: VIB-UGent Center for Medical Biotechnology
Maximilian Billmann: University of Minnesota-Twin Cities
Hadi Boukhatmi: Université de Rennes 1, CNRS, UMR6290
Barbara Kellen: Universidade do Algarve
Michael Costanzo: University of Toronto
Adrian Drazic: University of Bergen
Camilla Osberg: University of Bergen
Katherine Chan: University of Toronto
Xiang Zhang: University of Minnesota-Twin Cities
Amy Hin Yan Tong: University of Toronto
Simonetta Andreazza: University of Cambridge
Juliette J. Lee: University of Cambridge
Lyudmila Nedyalkova: University of Toronto
Matej Ušaj: University of Toronto
Alexander J. Whitworth: University of Cambridge
Brenda J. Andrews: University of Toronto
Jason Moffat: University of Toronto
Chad L. Myers: University of Minnesota-Twin Cities
Kris Gevaert: VIB-UGent Center for Medical Biotechnology
Charles Boone: University of Toronto
Rui Gonçalo Martinho: Universidade do Algarve
Thomas Arnesen: University of Bergen

Nature Communications, 2023, vol. 14, issue 1, 1-27

Abstract: Abstract Most 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42342-y

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DOI: 10.1038/s41467-023-42342-y

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