The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators

Hu, Rong Gui; Sheng, Jun; Qi, Xin; Xu, Zhenming; Takahashi, Terry T.; Varshavsky, Alexander

doi:10.1038/nature04027

Cited by 285 publications

(400 citation statements)

References 41 publications

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“…Similar results were obtained with the cells that stably expressed ANXA1-mEGFP fu -mRFP f fusion, consistent with the previous observation that ANXA1 protein was highly stable in vivo [33]. RGS4 (regulator of G-protein signaling 4) protein, a bona fide substrate that we have identified for the N-end rule pathway and proteasome [34], is highly unstable. As shown in Figure 1D, the ratio of fluorescence intensities of RGS4-mEG-FP fu and mRFP f , [RGS4-mEGFP fu ]/[mRFP f ], was low in cells that stably expressed the fluorescence-tagged RGS4 (RGS4-mEGFP fu -mRFP f ), but significantly increased upon BTZ treatment, indicating that degradation of RGS4 was proteasome dependent.…”

Section: The Protasupporting

confidence: 91%

Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

Tao

Yang

et al. 2014

Cell Res

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Global change in protein turnover (protein degradome) constitutes a central part of cellular responses to intrinsic or extrinsic stimuli. However, profiling protein degradome remains technically challenging. Recently, inhibition of the proteasome, e.g., by using bortezomib (BTZ), has emerged as a major chemotherapeutic strategy for treating multiple myeloma and other human malignancies, but systematic understanding of the mechanisms for BTZ drug action and tumor drug resistance is yet to be achieved. Here we developed and applied a dual-fluorescence-based Protein Turnover Assay (ProTA) to quantitatively profile global changes in human protein degradome upon BTZ-induced proteasomal inhibition. ProTA and subsequent network analyses delineate potential molecular basis for BTZ action and tumor drug resistance in BTZ chemotherapy. Finally, combined use of BTZ with drugs targeting the ProTA-identified key genes or pathways in BTZ action reduced BTZ resistance in multiple myeloma cells. Remarkably, BTZ stabilizes proteasome subunit PSMC1 and proteasome assembly factor PSMD10, suggesting a previously under-appreciated mechanism for regulating proteasome homeostasis. Therefore, ProTA is a novel tool for profiling human protein degradome to elucidate potential mechanisms of drug action and resistance, which might facilitate therapeutic development targeting proteostasis to treat human disorders.

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Section: The Protasupporting

confidence: 91%

Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

Tao

Yang

et al. 2014

Cell Res

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“…eNOS as a hypertrophy modulator. NO may play a role in mediation of hypertrophy because of its effect on degradation of regulators of G-protein signaling (RGS) proteins (10). Increased production of cGMP in the hearts of mice expressing both α-MHC-tTA and TRE-PR39 transgenes, resulting in tTA-driven myocyte-specific PR39 expression (tTA/PR39 mice) ( Figure 6A), suggested the possibility that increased NO production due to increased endothelial cell mass may mediate the observed hypertrophy.…”

Section: Inducible Pr39 Expression In Vitro and In Vivomentioning

confidence: 99%

Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice

Tı̂rziu¹,

Chorianopoulos²,

Moodie³

et al. 2007

J. Clin. Invest.

132

126

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Although studies have suggested a role for angiogenesis in determining heart size during conditions demanding enhanced cardiac performance, the role of EC mass in determining the normal organ size is poorly understood. To explore the relationship between cardiac vasculature and normal heart size, we generated a transgenic mouse with a regulatable expression of the secreted angiogenic growth factor PR39 in cardiomyocytes. A significant change in adult mouse EC mass was apparent by 3 weeks following PR39 induction. Heart weight; cardiomyocyte size; vascular density normalization; upregulation of hypertrophy markers including atrial natriuretic factor, β-MHC, and GATA4; and activation of the Akt and MAP kinase pathways were observed at 6 weeks post-induction. Treatment of PR39-induced mice with the eNOS inhibitor l-NAME in the last 3 weeks of a 6-week stimulation period resulted in a significant suppression of heart growth and a reduction in hypertrophic marker expression. Injection of PR39 or another angiogenic growth factor, VEGF-B, into murine hearts during myocardial infarction led to induction of myocardial hypertrophy and restoration of myocardial function. Thus stimulation of vascular growth in normal adult mouse hearts leads to an increase in cardiac mass.

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“…19 These outcomes indicate that a single component of the N-end rule pathway may be involved in multiple layers of regulatory circuits, probably in temporal cooperation with various downstream regulators of the pathway, such as the UBR proteins. The biological functions of these UBR proteins include the regulation of cardiovascular development, 17 chromosomal stability, 20 spermatogenesis, 21 oxygen sensing, 22 muscle wasting, [23][24][25][26] proteotoxic protein clearance, 27 hypertension, 28 neuronal tube formation, 29 bacterial/viral virulence, 30 and apoptosis. 31 More recent studies have suggested that the Arg/N-end rule pathway is also implicated in autophagy and mitophagy.…”

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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The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators

Cited by 285 publications

References 41 publications

Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice

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

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