The eukaryotic N-end rule pathway: conserved mechanisms and diverse functions

•The N-end rule targets protein substrates for ubiquitin-mediated degradation via their amino-termini.•The pathway regulates functionally diverse substrates and processes in eukaryotes.•Almost all protein amino-termini can impact on protein stability.•Oxygen and NO sensing are mediated by the N-end rule through kingdom-specific substrates.

The N-end rule pathway of targeted proteolysis, which relates the stability of a protein to the nature of its N-terminus, has emerged as a key regulator of diverse processes in eukaryotes. Recent reports that N-terminally acetylated and methionine-initiating proteins can be targeted for degradation have uncovered novel branches of the pathway, and a wide range of protein substrates has now been identified in animals, fungi, and plants. Of particular interest is the finding that the N-end rule pathway mediates oxygen and nitric oxide (NO) sensing in plants and animals by controlling the stability of kingdom-specific substrates. These findings highlight how conserved degradation mechanisms of the N-end rule pathway underlie functional divergence throughout eukaryotes.