Physiological functions and clinical implications of the N-end rule pathway

doi:10.1007/s11684-016-0458-7

Front. Med.

2016, Vol. 10

Issue (3) : 258-270 https://doi.org/10.1007/s11684-016-0458-7

REVIEW

Physiological functions and clinical implications of the N-end rule pathway

Yujiao Liu^1,²,Chao Liu^2,³,Wen Dong^1,^*(

),Wei Li^2,^*(

)

¹. College of Marine Life, Ocean University of China, Qingdao 266003, China
². State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
³. University of Chinese Academy of Sciences, Beijing 100049, China

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Abstract

The N-end rule pathway is a unique branch of the ubiquitin-proteasome system in which the determination of a protein’s half-life is dependent on its N-terminal residue. The N-terminal residue serves as the degradation signal of a protein and thus called N-degron. N-degron can be recognized and modifed by several steps of post-translational modifications, such as oxidation, deamination, arginylation or acetylation, it then polyubiquitinated by the N-recognin for degradation. The molecular basis of the N-end rule pathway has been elucidated and its physiological functions have been revealed in the past 30 years. This pathway is involved in several biological aspects, including transcription, differentiation, chromosomal segregation, genome stability, apoptosis, mitochondrial quality control, cardiovascular development, neurogenesis, carcinogenesis, and spermatogenesis. Disturbance of this pathway often causes the failure of these processes, resulting in some human diseases. This review summarized the physiological functions of the N-end rule pathway, introduced the related biological processes and diseases, with an emphasis on the inner link between this pathway and certain symptoms.

Keywords N-end rule pathway Ate1 cardiovascular development neurogenesis spermatogenesis neurodegenerative disorders Johanson–Blizzard syndrome

Corresponding Author(s): Wen Dong,Wei Li

Just Accepted Date: 05 July 2016 Online First Date: 04 August 2016 Issue Date: 30 August 2016

Cite this article:

Yujiao Liu,Chao Liu,Wen Dong, et al. Physiological functions and clinical implications of the N-end rule pathway[J]. Front. Med., 2016, 10(3): 258-270.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-016-0458-7
https://academic.hep.com.cn/fmd/EN/Y2016/V10/I3/258

Fig.1 Mammalian N-end rule pathway. (A) Mammalian Ac/N-end rule pathway. This pathway targets proteins through their N^α-terminally acetylated residues. The red arrow on the left indicates the co-translational removal of the initiator Met by Met-aminopeptidases (MetAPs). The N-terminal Met is retained when a residue at position 2 is larger than Val. (B) Mammalian Arg/N-end rule pathway. This pathway targets proteins for degradation through their specific unacetylated N-terminal residues. ATE1 is arginyl-tRNA-protein transferase. “Primary,” “secondary,” and “tertiary” refer to mechanistically distinct classes of destabilizing N-terminal residues. “Type I” and “Type II” refer to two sets of primary destabilizing N-terminal residues: basic and bulky hydrophobic, respectively.

Tab.1 Representative substrates of the mammalian N-end rule pathway

Fig.2 Major biological function of the N-end rule pathway. The main biological functions of the N-end rule pathway include transcription through the degradation of IkBa and c-Fos, differentiation through the degradation of a growing factor Igfbp2, genome stability through the degradation of Scc1 and H2A, apoptosis through the degradation of a series of apoptotic proteins, mitochondrial quality control through the degradation of PINK, cardiovascular development through the degradation of RGS proteins, and spermatogenesis through the degradation of REC8.

Fig.3 Role of N-end rule pathway-mediated degradation of RGS proteins in cardiovascular development. G-protein coupled receptor (GPCR) transfers extracellular signals to the intracellular environment by dissolving heterotrimeric G-proteins and forming active Gα-GTP to stimulate downstream signal pathways. The RGS family acts as GTPase-activating proteins. As a result, the concentration of Gα-GTP in the cytosol decreases and downstream signaling is blocked.

Fig.4 Functional role of the N-end rule pathway in spermatogenesis. The N-end rule pathway participates in multiple stages of spermatogenesis. In prophase I, UBR1 facilitates the ubiquitination of H2A and H2B to maintain proper transcription and thus allow spermatocytes to bypass the pachytene checkpoint. In metaphase, the Ate1-mediated arginylation of the fragment of Rec8 cleaved by separase is required for its degradation. In spermiogenesis, histone replacement by protamine requires HR6B, which is the E2 of the N-end rule pathway.

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[1]	Raafat Hegazy,Abdelmonem Hegazy,Mustafa Ammar,Emad Salem. Immunohistochemical measurement and expression of Mcl-1 in infertile testes[J]. Front. Med., 2015, 9(3): 361-367.

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