Fig. 8. N-terminal acetylation by NatC shields proteins from degradation by preventing N-recognin UBR4-KCMF1 targeting.

(Left) The NatC complex co-translationally acetylates proteins harboring a hydrophobic residue in the second position (MΦ-). Following Nt-acetylation, the NEDD8 E2 ligases Ac-UBE2M and Ac-UBE2F promote cullin neddylation (N8), resulting in ubiquitylation (Ub) and proteasomal degradation of targeted cullin substrates, Ac-ARFRP1 is targeted to the Golgi where it plays a role in the secretory pathway, while the hypothetical proteins Ac-X and Ac-Y are thought to affect the secretory pathway and mitochondria, respectively. (Right) Loss of NatC exposes unacetylated MΦ-starting N-termini which serves as N-degrons that can be recognized by a set of N-recognins leading to proteasomal and, in some cases, lysosomal degradation. Non-Nt-acetylated NatC substrates are primarily targeted by the Arg/N-recognin UBR4-KCMF1 and to some extent via UBR1 and UBR2. Targeted degradation of non-Nt-acetylated NatC substrates leads to decreased cullin neddylation, increased mitochondrial elongation and fragmentation, and is thought to affect intracellular trafficking.