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Pharmacological Modulation of the N-End Rule Pathway and Its Therapeutic Implications.

ABSTRACT: The N-end rule pathway is a proteolytic system in which single N-terminal amino acids of short-lived substrates determine their metabolic half-lives. Substrates of this pathway have been implicated in the pathogenesis of many diseases, including malignancies, neurodegeneration, and cardiovascular disorders. This review provides a comprehensive overview of current knowledge about the mechanism and functions of the N-end rule pathway. Pharmacological strategies for the modulation of target substrate degradation are also reviewed, with emphasis on their in vivo implications. Given the rapid advances in structural and biochemical understanding of the recognition components (N-recognins) of the N-end rule pathway, small-molecule inhibitors and activating ligands of N-recognins emerge as therapeutic agents with novel mechanisms of action.

SUBMITTER: Lee JH

PROVIDER: S-EPMC4641009 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Pharmacological Modulation of the N-End Rule Pathway and Its Therapeutic Implications.

Lee Jung Hoon JH Jiang Yanxialei Y Kwon Yong Tae YT Lee Min Jae MJ

Trends in pharmacological sciences 20151001 11

The N-end rule pathway is a proteolytic system in which single N-terminal amino acids of short-lived substrates determine their metabolic half-lives. Substrates of this pathway have been implicated in the pathogenesis of many diseases, including malignancies, neurodegeneration, and cardiovascular disorders. This review provides a comprehensive overview of current knowledge about the mechanism and functions of the N-end rule pathway. Pharmacological strategies for the modulation of target substra ...[more]

PMID: 26434644

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The N-end rule pathway.

Project description:The N-end rule pathway is a proteolytic system in which N-terminal residues of short-lived proteins are recognized by recognition components (N-recognins) as essential components of degrons, called N-degrons. Known N-recognins in eukaryotes mediate protein ubiquitylation and selective proteolysis by the 26S proteasome. Substrates of N-recognins can be generated when normally embedded destabilizing residues are exposed at the N terminus by proteolytic cleavage. N-degrons can also be generated through modifications of posttranslationally exposed pro-N-degrons of otherwise stable proteins; such modifications include oxidation, arginylation, leucylation, phenylalanylation, and acetylation. Although there are variations in components, degrons, and hierarchical structures, the proteolytic systems based on generation and recognition of N-degrons have been observed in all eukaryotes and prokaryotes examined thus far. The N-end rule pathway regulates homeostasis of various physiological processes, in part, through interaction with small molecules. Here, we review the biochemical mechanisms, structures, physiological functions, and small-molecule-mediated regulation of the N-end rule pathway.

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PINK1 is degraded through the N-end rule pathway.

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Project description:Microarray experiments to compare gene expression profiles of ate1 ate2 double-mutant plants and the wild type at different developmental stages and after the infiltration with Pseudomonas syringae strain Pst AvrRpm1.

2016-05-02 | GSE80275 | GEO

The N-end rule pathway regulates pathogen responses in plants.

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Pharmacological modulation of GITRL/GITR system: therapeutic perspectives.

Project description:Glucocorticoid-induced TNFR-related (gitr) is a gene coding for a member of the TNF receptor superfamily. GITR activation by its ligand (GITRL) influences the activity of effector and regulatory T cells, thus participating in the development of immune response against tumours and infectious agents, as well as in autoimmune and inflammatory diseases. Notably, treating animals with GITR-Fc fusion protein ameliorates autoimmune/inflammatory diseases while GITR triggering, by treatment with anti-GITR mAb, is effective in treating viral, bacterial and parasitic infections, as well in boosting immune response against tumours. GITR modulation has been indicated as one of the top 25 most promising research areas by the American National Cancer Institute, and a clinical trial testing the efficacy of an anti-GITR mAb in melanoma patients has been started. In this review, we summarize results regarding: (i) the mechanisms by which GITRL/GITR system modulates immune response; (ii) the structural and functional studies clearly demonstrating differences between GITRL/GITR systems of mice and humans; (iii) the molecules with pharmacological activities including anti-GITR mAbs, GITR-Fc and GITRL-Fc fusion proteins, GITRL in monomer or multimer conformation; and (iv) the possible risks deriving from GITRL/GITR system pharmacological modulation. In conclusion, GITR triggering and inhibition could be useful in treating tumours, infectious diseases, as well as autoimmune and inflammatory diseases. However, differences between mouse and human GITRL/GITR systems suggest that further preclinical studies are needed to better understand how safe therapeutic results can be obtained and to design appropriate clinical trials.

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N-end rule pathway inhibition assists colon tumor regression via necroptosis.

Project description:Recent study has shown that N-end rule pathway, an ubiquitin dependent proteolytic system, counteracts cell death by degrading many antisurvival protein fragments like BCLxL, BRCA1, RIPK1, etc. Inhibition of the N-end rule pathway can lead to metabolic stabilization of proapoptotic protein fragments like RIPK1, thereby sensitizing cells to programmed cell death. Receptor interacting serine-threonine protein kinase-1 (RIPK1) is one of the upstream regulators of programmed necrosis known as necroptosis. Necroptosis is particularly gaining attention of cancer biologists as it provides an alternate therapeutic modality to kill cancer cells, which often evolve multiple strategies to circumvent growth inhibition by apoptosis. Utilizing the over expression of biotin receptor in cancer cells, herein, we report that coadministration of synthetic hetero-bivalent N-end rule inhibitor RFC11 and anticancer drug shikonin solubilized in a stable biotin receptor-targeted liposome exhibited significant synergistic antitumor effect in both subcutaneous and orthotopic mouse colon tumor model through induction of necroptosis with distinctive upregulation of RIPK1. Besides developing a newly targeted formulation for necroptosis induction, this report is the first in vivo evidence demonstrating that potent inhibition of N-end rule pathway can enhance therapeutic efficacy of conventional chemotherapeutics.

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An N-end rule pathway that recognizes proline and destroys gluconeogenic enzymes.

Project description:Cells synthesize glucose if deprived of it, and destroy gluconeogenic enzymes upon return to glucose-replete conditions. We found that the Gid4 subunit of the ubiquitin ligase GID in the yeast Saccharomyces cerevisiae targeted the gluconeogenic enzymes Fbp1, Icl1, and Mdh2 for degradation. Gid4 recognized the N-terminal proline (Pro) residue and the ~5-residue-long adjacent sequence motifs. Pck1, the fourth gluconeogenic enzyme, contains Pro at position 2; Gid4 directly or indirectly recognized Pro at position 2 of Pck1, contributing to its targeting. These and related results identified Gid4 as the recognition component of the GID-based proteolytic system termed the Pro/N-end rule pathway. Substrates of this pathway include gluconeogenic enzymes that bear either the N-terminal Pro residue or a Pro at position 2, together with adjacent sequence motifs.

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A picorna-like virus suppresses the N-end rule pathway to inhibit apoptosis.

Project description:The N-end rule pathway is an evolutionarily conserved proteolytic system that degrades proteins containing N-terminal degradation signals called N-degrons, and has emerged as a key regulator of various processes. Viruses manipulate diverse host pathways to facilitate viral replication and evade antiviral defenses. However, it remains unclear if viral infection has any impact on the N-end rule pathway. Here, using a picorna-like virus as a model, we found that viral infection promoted the accumulation of caspase-cleaved Drosophila inhibitor of apoptosis 1 (DIAP1) by inducing the degradation of N-terminal amidohydrolase 1 (NTAN1), a key N-end rule component that identifies N-degron to initiate the process. The virus-induced NTAN1 degradation is independent of polyubiquitylation but dependent on proteasome. Furthermore, the virus-induced N-end rule pathway suppression inhibits apoptosis and benefits viral replication. Thus, our findings demonstrate that a virus can suppress the N-end rule pathway, and uncover a new mechanism for virus to evade apoptosis.

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