The N-end rule pathway: emerging functions and molecular principles of substrate recognition

Sriram, Shashikanth M.; Kim, Bo Yeon; Kwon, Yong Tae

doi:10.1038/nrm3217

Cited by 184 publications

(182 citation statements)

References 130 publications

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“…The N-end rule pathway uses the destabilizing amino-terminal residues of proteins as essential determinants (N-degrons) of their half-lives in vivo. 1,2 The N-degrons are the first defined degradation signals in eukaryotes and have later been identified even in bacteria, which lack Ub. 3,4 These findings suggest that N-degron-dependent proteolysis may be an evolutionary precursor of nature's selective degradation machinery through the "chambered proteases" in the cell.…”

Section: Introductionmentioning

confidence: 99%

The arginylation branch of the N-end rule pathway positively regulates cellular autophagic flux and clearance of proteotoxic proteins

Jiang

Lee

et al. 2016

Autophagy

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The N-terminal amino acid of a protein is an essential determinant of ubiquitination and subsequent proteasomal degradation in the N-end rule pathway. Using para-chloroamphetamine (PCA), a specific inhibitor of the arginylation branch of the pathway (Arg/N-end rule pathway), we identified that blocking the Arg/N-end rule pathway significantly impaired the fusion of autophagosomes with lysosomes. Under ER stress, ATE1-encoded Arg-tRNA-protein transferases carry out the N-terminal arginylation of the ER heat shock protein HSPA5 that initially targets cargo proteins, along with SQSTM1, to the autophagosome. At the late stage of autophagy, however, proteasomal degradation of arginylated HSPA5 might function as a critical checkpoint for the proper progression of autophagic flux in the cells. Consistently, the inhibition of the Arg/N-end rule pathway with PCA significantly elevated levels of MAPT and huntingtin aggregates, accompanied by increased numbers of LC3 and SQSTM1 puncta. Cells treated with the Arg/N-end rule inhibitor became more sensitized to proteotoxic stress-induced cytotoxicity. SILAC-based quantitative proteomics also revealed that PCA significantly alters various biological pathways, including cellular responses to stress, nutrient, and DNA damage, which are also closely involved in modulation of autophagic responses. Thus, our results indicate that the Arg/N-end rule pathway may function to actively protect cells from detrimental effects of cellular stresses, including proteotoxic protein accumulation, by positively regulating autophagic flux.

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Section: Introductionmentioning

confidence: 99%

The arginylation branch of the N-end rule pathway positively regulates cellular autophagic flux and clearance of proteotoxic proteins

Jiang

Lee

et al. 2016

Autophagy

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“…In addition to type-1 and type-2 N-degrons, a recent study reported that acetylated N-terminal residues, occurring at 80% of human proteins, can function as N-degrons (13). The functions of the N-end rule pathway in degradation of short-lived proteins carrying N-degrons have been characterized in various processes (2,3). One outstanding question in the N-end rule pathway concerns differential functions of N-recognins that share binding specificity to N-terminal residues.…”

mentioning

confidence: 99%

UBR box N-recognin-4 (UBR4), an N-recognin of the N-end rule pathway, and its role in yolk sac vascular development and autophagy

Tasaki

Kim

Zakrzewska

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The N-end rule pathway is a proteolytic system in which destabilizing N-terminal residues of short-lived proteins act as degradation determinants (N-degrons). Substrates carrying N-degrons are recognized by N-recognins that mediate ubiquitylation-dependent selective proteolysis through the proteasome. Our previous studies identified the mammalian N-recognin family consisting of UBR1/ E3α, UBR2, UBR4/p600, and UBR5, which recognize destabilizing N-terminal residues through the UBR box. In the current study, we addressed the physiological function of a poorly characterized N-recognin, 570-kDa UBR4, in mammalian development. UBR4-deficient mice die during embryogenesis and exhibit pleiotropic abnormalities, including impaired vascular development in the yolk sac (YS). Vascular development in UBR4-deficient YS normally advances through vasculogenesis but is arrested during angiogenic remodeling of primary capillary plexus associated with accumulation of autophagic vacuoles. In the YS, UBR4 marks endoderm-derived, autophagy-enriched cells that coordinate differentiation of mesoderm-derived vascular cells and supply autophagy-generated amino acids during early embryogenesis. UBR4 of the YS endoderm is associated with a tissue-specific autophagic pathway that mediates bulk lysosomal proteolysis of endocytosed maternal proteins into amino acids. In cultured cells, UBR4 subpopulation is degraded by autophagy through its starvation-induced association with cellular cargoes destined to autophagic double membrane structures. UBR4 loss results in multiple misregulations in autophagic induction and flux, including synthesis and lipidation/activation of the ubiquitin-like protein LC3 and formation of autophagic double membrane structures. Our results suggest that UBR4 plays an important role in mammalian development, such as angiogenesis in the YS, in part through regulation of bulk degradation by lysosomal hydrolases. cardiovascular system | ubiquitin ligase

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“…N-degrons are generated within the cell when specific residues are exposed at the N terminus by proteolytic cleavage. There are two classes of destabilizing N-degrons: positively charged amino acids (Arg, Lys, and His) are of type 1, and bulky hydrophobic ones (Phe, Trp, Tyr, Leu, and Ile) are of type 2 [13].…”

Section: N-degronsmentioning

confidence: 99%

“…1a) (Fig 1b and 1c) [13,18,19]. In eukaryotes, the default N-terminal amino acid is Met (Nformylmethionine in bacteria).…”

Section: N-degronsmentioning

confidence: 99%

Recognition of substrate degrons by E3 ubiquitin ligases and modulation by small-molecule mimicry strategies

Lucas

Ciulli

2017

Current Opinion in Structural Biology

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The N-end rule pathway: emerging functions and molecular principles of substrate recognition

Cited by 184 publications

References 130 publications

The arginylation branch of the N-end rule pathway positively regulates cellular autophagic flux and clearance of proteotoxic proteins

The arginylation branch of the N-end rule pathway positively regulates cellular autophagic flux and clearance of proteotoxic proteins

UBR box N-recognin-4 (UBR4), an N-recognin of the N-end rule pathway, and its role in yolk sac vascular development and autophagy

Recognition of substrate degrons by E3 ubiquitin ligases and modulation by small-molecule mimicry strategies

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