The N-end rule relates the regulation of the in vivo half-life of a protein to 
the identity of its N-terminal residue. Degradation signals (degrons) that are 
targeted by the N-end rule pathway include a set called N-degrons. The main 
determinant of an N-degron is a destabilizing N-terminal residue of a protein. 
In eukaryotes, the N-end rule pathway is a part of the ubiquitin system and 
consists of two branches, the Ac/N-end rule and the Arg/N-end rule pathways. The 
Ac/N-end rule pathway targets proteins containing N(α) -terminally acetylated 
(Nt-acetylated) residues. The Arg/N-end rule pathway recognizes unacetylated 
N-terminal residues and involves N-terminal arginylation. Together, these 
branches target for degradation a majority of cellular proteins. For example, 
more than 80% of human proteins are cotranslationally Nt-acetylated. Thus most 
proteins harbor a specific degradation signal, termed (Ac)N-degron, from the 
moment of their birth. Specific N-end rule pathways are also present in 
prokaryotes and in mitochondria. Enzymes that produce N-degrons include 
methionine-aminopeptidases, caspases, calpains, Nt-acetylases, Nt-amidases, 
arginyl-transferases and leucyl-transferases. Regulated degradation of specific 
proteins by the N-end rule pathway mediates a legion of physiological functions, 
including the sensing of heme, oxygen, and nitric oxide; selective elimination 
of misfolded proteins; the regulation of DNA repair, segregation and 
condensation; the signaling by G proteins; the regulation of peptide import, fat 
metabolism, viral and bacterial infections, apoptosis, meiosis, spermatogenesis, 
neurogenesis, and cardiovascular development; and the functioning of adult 
organs, including the pancreas and the brain. Discovered 25 years ago, this 
pathway continues to be a fount of biological insights.