Progress on the role of N-end rule pathways in protein degradation
The N-end rule pathway is a protein degradation pathway mediated by the ubiquitin-proteasome system,which specifically targets and degrades target proteins by recognizing specific residues at the N-terminus of the proteins.The residues which play a crucial role in the N-end rule pathway are called degrons,also known as N-degrons,as they are usually unstable at the N-terminal end of the protein.Currently,several N-end rule pathways have been identified in the eukaryotes,including the Arg/N-end rule,Ac/N-end rule,and Pro/N-end rule pathways,as well as the recently discovered Gly/N-end rule pathway.The Ac/N-end rule pathway targets proteins containing N-terminal acetylation(Nt-acetylation)residues.The Arg/N-end rule pathway,on the other hand,targets certain unacetylated residues and involves N-terminal arginylation.For proteins with N-terminal proline(Pro)and glycine(Gly)residues,they are neither modified by acetylation nor recognized through the Arg/N-end rule pathway.Therefore,these proteins are primarily recognized and degraded through the Pro/N-end rule pathway and the Gly/N-end rule pathway.The regulation of specific proteins through N-end rule pathway-mediated degradation plays an important role in numerous physiological and pathological processes,such as cardiovascular development,neurogenesis,meiosis,spermatogenesis,HPV infection,and cell apoptosis.In this review,we summarize the role and mechanisms of several known N-end rule pathways and discuss their relationship with certain diseases.As an independent protein degradation system,the N-end rule pathways still hold countless biological secrets waiting for exploring.The comprehensive understanding of these pathways could potentially uncover novel therapeutic targets for various diseases.
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