In eukaryotic cells, regulated protein degradation of intracellular proteins is 
mediated largely by the ubiquitin proteasome system (UPS). UPS-mediated protein 
degradation regulates virtually all crucial aspects of cellular physiology, such 
as cell proliferation, cell division, cell differentiation, and cell death. 
Concomitantly, the deregulation by the UPS contributes to human disorders 
including cancer. Cellular regulation by UPS- mediated protein degradation is a 
highly specific and selective process that depends on time (e.g. cell cycle) and 
location (nucleus, mitochondria or endoplasmic reticulum). An ongoing challenge 
in the protein degradation field is identification of degradation signals for 
specific proteins that trigger their degradation by the proteasome. More than 25 
years ago, the first degradation signal was discovered and defined as 
destabilizing N-terminal amino-acid residue (or N-degron) of protein substrates. 
The discovery and subsequent detailed analysis of N-degrons gave rise to the so 
called N-end rule, which states that the half-life time of a protein is 
determined by the identity of its N-terminal amino-acid residue. The N-end rule 
pathway recognizes proteins containing N-terminal destabilizing residues and 
mediates their polyubiquitination and subsequent degradation in the proteasome. 
Recent investigations have revealed a role for N-terminal acetylation on the 
recognition of N-degrons by the N-end rule pathway. Here we summarize these 
recent findings and highlight the impact on our understanding of the N-end rule 
pathway with respect to cellular physiology.