N-Terminal Acetylation of Cellular Proteins Creates Specific Degradation Signals

Hwang, Cheol-Sang; Smerdel-Ramoya, Anna; Varshavsky, Alexander

doi:10.1126/science.1183147

Cited by 578 publications

(756 citation statements)

References 29 publications

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“…FOXO3a protein can be degraded by AKTtriggered ubiquitination-proteasome pathway (Plas and Thompson, 2003) or by caspase-3-like proteases in hematopoietic cells (Charvet et al, 2003). Recently, it is shown that N-terminal acetylation of cellular proteins creates specific degradation signals targeted by ubiquitin-dependent proteasome pathway (Hwang et al, 2010). As the NAMPT inhibition reduces sirtuin deacetylase activity, it is possible that N-terminal acetylation of certain proteins may be increased for degradation.…”

Section: Discussionmentioning

confidence: 99%

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

et al. 2010

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Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in regenerating nicotinamide adenine dinucleotide (NAD þ ) from nicotinamide in mammals. NAMPT has crucial roles for many cellular functions by regulating NAD þ -dependent SIRT1 deacetylase. However, roles of NAMPT in cancer are poorly defined. In this study, we show that NAMPT is prominently overexpressed in human prostate cancer cells along with SIRT1. Elevation of NAMPT expression occurs early for the prostate neoplasia. Inhibition of NAMPT significantly suppresses cell growth in culture, soft agar colony formation, cell invasion and growth of xenografted prostate cancer cells in mice. NAMPT knockdown sensitizes prostate cancer cells to oxidative stress caused by H 2 O 2 or chemotherapeutic treatment. Overexpression of NAMPT increases prostate cancer cell resistance to oxidative stress, which is partially blocked by SIRT1 knockdown. We demonstrate that in addition to modulating SIRT1 functions, the NAMPT inhibition reduces forkhead box, class 'O' (FOXO)3a protein expression and its downstream anti-oxidant genes catalase and manganese superoxide dismutase. Our results suggest important roles of concomitant upregulation of NAMPT and SIRT1 along with increased FOXO3a protein level for prostate carcinogenesis and their contribution to oxidative stress resistance of prostate cancer cells. These findings may have implications for exploring the NAMPT pathway for prostate cancer prevention and treatment.

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Section: Discussionmentioning

confidence: 99%

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

et al. 2010

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“…The biological significance of N-terminal acetylation is still unclear, because no global trend regarding the functional consequences of N-terminal acetylation emerges. For some proteins, N-terminal acetylation may act as a degradation signal (88), whereas for others N-terminal acetylation may protect from proteolytic degradation and subsequently increases their half-life (89). N-terminal acetylation was also shown to be involved in protein sorting and addressing to cellular organelles (90) or to membrane (91).…”

Section: Discussionmentioning

confidence: 99%

Linking Post-Translational Modifications and Variation of Phenotypic Traits

Albertin

Marullo

Bely

et al. 2013

Molecular & Cellular Proteomics

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Enzymes can be post-translationally modified, leading to isoforms with different properties. The phenotypic consequences of the quantitative variability of isoforms have never been studied. We used quantitative proteomics to dissect the relationships between the abundances of the enzymes and isoforms of alcoholic fermentation, metabolic traits, and growth-related traits in Saccharomyces cerevisiae. Although the enzymatic pool allocated to the fermentation proteome was constant over the culture media and the strains considered, there was variation in abundance of individual enzymes and sometimes much more of their isoforms, which suggests the existence of selective constraints on total protein abundance and trade-offs between isoforms. Variations in abundance of some isoforms were significantly associated to metabolic traits and growth-related traits. In particular, cell size and maximum population size were highly correlated to the degree of N-terminal acetylation of the alcohol dehydrogenase. The fermentation proteome was found to be shaped by human selection, through the differential targeting of a few isoforms for each food-processing origin of strains. These results highlight the importance of posttranslational modifications in the diversity of metabolic and life-history traits. Molecular & Cellular Proteomics 12: 10.1074/mcp.M112.024349, 720 -735, 2013.The key problem in understanding genotype-phenotype relationships is the complexity arising from multiple levels of cellular functioning. Among them, metabolic networks involve series of interconnected chemical reactions catalyzed by enzymes, allowing the transformation of input substrates into intermediate or final metabolites. These networks play an essential role in an organism's growth, reproduction, and ability to maintain cell integrity and to respond to environmental changes (1, 2). The metabolic fluxes, as well as the metabolite concentrations, are governed by the activity of the enzymes, which depends on three types of factors: kinetic parameters, enzyme abundance, and activation state of the enzyme. The kinetic parameters are determined by the sequence and the three-dimensional structure of the protein (3). The abundance of the enzymes is the result of numerous molecular processes taking place from the transcriptional to the translational level, including epigenetic modifications of the DNA and chromatin (4), transcriptional regulation by transcription factors (5), mRNA capping and splicing and small RNA regulation (6), protein turnover (7), etc. The enzyme activation state is primarily because of post-translational modifications of the native protein, themselves highly regulated (8, 9). Other mechanisms involved in enzyme activity are proteinprotein interactions and allosteric regulation, such mechanisms being sometimes mediated through post-translational modifications (10, 11). The resulting isoforms can display differences in activity, affinity for partners (protein or effectors), and stability (12). The most studied modification is the reversibl...

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“…Our observation may therefore indicate a general modification pathway for plastid proteins in the cytosol. N-acetylation serves as a degradation signal for the ubiquitin ligase-proteasome system in yeast, and it was proposed to be involved in protein folding quality control (Hwang et al, 2010). Support for a function of plastid precursor protein N-acetylation in vivo came from the characterization of a mutant for a cytoplasmic N-acetyltransferase.…”

Section: N-terminal Met Excision and Acetylation Of Plastid Precursormentioning

confidence: 99%

Plastid Proteome Assembly without Toc159: Photosynthetic Protein Import and Accumulation of N-Acetylated Plastid Precursor Proteins

et al. 2011

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Import of nuclear-encoded precursor proteins from the cytosol is an essential step in chloroplast biogenesis that is mediated by protein translocon complexes at the inner and outer envelope membrane (TOC). Toc159 is thought to be the main receptor for photosynthetic proteins, but lacking a large-scale systems approach, this hypothesis has only been tested for a handful of photosynthetic and nonphotosynthetic proteins. To assess Toc159 precursor specificity, we quantitatively analyzed the accumulation of plastid proteins in two mutant lines deficient in this receptor. Parallel genomewide transcript profiling allowed us to discern the consequences of impaired protein import from systemic transcriptional responses that contribute to the loss of photosynthetic capacity. On this basis, we defined putative Toc159-independent and Toc159-dependent precursor proteins. Many photosynthetic proteins accumulate in Toc159-deficient plastids, and, surprisingly, several distinct metabolic pathways are negatively affected by Toc159 depletion. Lack of Toc159 furthermore affects several proteins that accumulate as unprocessed N-acetylated precursor proteins outside of plastids. Together, our data show an unexpected client protein promiscuity of Toc159 that requires a far more differentiated view of Toc159 receptor function and regulation of plastid protein import, in which cytosolic Met removal followed by N-terminal acetylation of precursors emerges as an additional regulatory step.

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N-Terminal Acetylation of Cellular Proteins Creates Specific Degradation Signals

Cited by 578 publications

References 29 publications

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

Linking Post-Translational Modifications and Variation of Phenotypic Traits

Plastid Proteome Assembly without Toc159: Photosynthetic Protein Import and Accumulation of N-Acetylated Plastid Precursor Proteins

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