Biological regulation by N-terminal acetylation

Obiettivo

Reversible protein modifications act as key switches regulating numerous cellular processes. In contrast, our most abundant protein modification, N-terminal (Nt) acetylation, has for decades been considered static and irreversible. This project aims to identify regulatory Nt-acetylation events (Nt-switches) and establish their crucial role in human biology.

A relevant place to look for Nt-switches is at neo-N-termini. These are generated by proteases, for example the signal peptide cleavage of proteins entering the endoplasmic reticulum (ER), or the maturation of bioactive peptides in the secretory pathway. The bioactive peptides that regulate appetite and pain are particularly interesting since it is known that their neo-N-termini are Nt-acetylated, which has critical effects for their biological activity. ER chaperones are also Nt-acetylated, as our unpublished data has uncovered. This occurs in response to cellular stress when ER chaperones move to the cytosol. Here, Nt-acetylation competes with another Nt-modification to potentially control protein degradation, autophagy, cell migration and other stress responses. Our data also suggest that Nt-acetylation is dynamic and reversible, but the enzymes responsible for post-translational Nt-acetylation of bioactive peptides and ER-chaperones and protein Nt-deacetylation have not yet been identified. The biological regulation mediated by Nt-switches is therefore not yet mechanistically understood.

The objective of this project is to uncover how Nt-acetylation steers protein fate and how Nt-switches are involved in biological regulation. Our recently developed cell models, enzyme assays, modification-specific antibodies and biochemical, chemical biology and proteomics approaches will identify and define the human enzymes adding, removing or competing with Nt-acetylation. This project will establish the Nt-switch concept and unravel its impact on the processes of autophagy, cell migration and metabolism.