Browsing by Author "Arnesen, Thomas"
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- N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevityPublication . Varland, Sylvia; Silva, Rui Duarte; Kjosås, Ine; Faustino, Alexandra; Bogaert, Annelies; Billmann, Maximilian; Boukhatmi, Hadi; Kellen, Barbara; Costanzo, Michael; Drazic, Adrian; Osberg, Camilla; Chan, Katherine; Zhang, Xiang; Tong, Amy Hin Yan; Andreazza, Simonetta; Lee, Juliette J.; Nedyalkova, Lyudmila; Ušaj, Matej; Whitworth, Alexander J.; Andrews, Brenda J.; Moffat, Jason; Myers, Chad L.; Gevaert, Kris; Boone, Charles; Martinho, Rui Gonçalo; Arnesen, ThomasMost 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.
- Naa50/San-dependent N-terminal acetylation of Scc1 is potentially important for sister chromatid cohesionPublication . Ribeiro, Ana Luisa; Silva, Rui D.; Foyn, Havard; Tiago, Margarida N.; Rathore, Om; Arnesen, Thomas; Martinho, Rui GoncaloThe gene separation anxiety (san) encodes Naa50/San, a N-terminal acetyltransferase required for chromosome segregation during mitosis. Although highly conserved among higher eukaryotes, the mitotic function of this enzyme is still poorly understood. Naa50/San was originally proposed to be required for centromeric sister chromatid cohesion in Drosophila and human cells, yet, more recently, it was also suggested to be a negative regulator of microtubule polymerization through internal acetylation of beta Tubulin. We used genetic and biochemical approaches to clarify the function of Naa50/San during development. Our work suggests that Naa50/San is required during tissue proliferation for the correct interaction between the cohesin subunits Scc1 and Smc3. Our results also suggest a working model where Naa50/San N-terminally acetylates the nascent Scc1 polypeptide, and that this co-translational modification is subsequently required for the establishment and/or maintenance of sister chromatid cohesion.