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Progress on the role of N-end rule pathways in protein degradation

XU Na-Xin¹, LIU Yong¹, WANG Yi², LING Shu-Kuan^3,*

¹Academy of Sports Human Sciences, Beijing Sport University, Beijing 100084, China；²Department of Sports, Renmin University of China, Beijing 100872, China；³Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou 325000, China

Abstract

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.

Key words: N-end rule pathway; E3 ubiquitin ligase; ubiquitin-mediated degradation

Received: 　　Accepted:

Corresponding author: 凌树宽　　E-mail:

Citing This Article：

XU Na-Xin, LIU Yong, WANG Yi, LING Shu-Kuan. Progress on the role of N-end rule pathways in protein degradation. Acta Physiol Sin 2024; 76 (6): 987-1000 (in Chinese with English abstract).