The growing landscape of lysine acetylation links metabolism and cell signalling

Choudhary, Chunaram; Weinert, Brian T.; Nishida, Yuya; Verdin, Eric; Mann, Matthias

doi:10.1038/nrm3841

Cited by 1,111 publications

(1,007 citation statements)

References 169 publications

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“…Neither in vitro assays nor overexpression experiments can completely reproduce in vivo conditions, which makes it difficult to draw definite conclusions about the regulation of Ran acetylation in a physiological context. The limitations of these assays are to some extent also reflected by the fact that several additional Ran acetylation sites than those presented in this study can be found in available high-throughput MS data (23,54). However, further studies are required to gain insight into the regulation of Ran function by lysine acetylation in vivo.…”

Section: Discussionmentioning

confidence: 99%

Small GTP-binding protein Ran is regulated by posttranslational lysine acetylation

Boor

Knyphausen

Kuhlmann

et al. 2015

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

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Ran is a small GTP-binding protein of the Ras superfamily regulating fundamental cellular processes: nucleo-cytoplasmic transport, nuclear envelope formation and mitotic spindle assembly. An intracellular Ran•GTP/Ran•GDP gradient created by the distinct subcellular localization of its regulators RCC1 and RanGAP mediates many of its cellular effects. Recent proteomic screens identified five Ran lysine acetylation sites in human and eleven sites in mouse/rat tissues. Some of these sites are located in functionally highly important regions such as switch I and switch II. Here, we show that lysine acetylation interferes with essential aspects of Ran function: nucleotide exchange and hydrolysis, subcellular Ran localization, GTP hydrolysis, and the interaction with import and export receptors. Deacetylation activity of certain sirtuins was detected for two Ran acetylation sites in vitro. Moreover, Ran was acetylated by CBP/p300 and Tip60 in vitro and on transferase overexpression in vivo. Overall, this study addresses many important challenges of the acetylome field, which will be discussed.Ran | lysine acetylation | genetic code expansion concept | nucleus | nuclear cytosolic transport T he small GTP-binding protein Ran (Ras-related nuclear) is involved in nucleo-cytoplasmic transport processes, nuclear envelope formation, and the formation of the mitotic spindle (1). Ran, furthermore, has a variety of cytosolic functions and is involved in the cross-talk with the actin cytoskeleton. As a member of the Ras superfamily, Ran is structurally composed of a fold known as the G-domain (GTP-binding domain), a central sixstranded β-sheet that is surrounded by α-helices. Ras-family members bind to GTP and GDP nucleotides with high picomolar affinity. However, only in the GTP-bound form and the switch Iand switch II-loops adopt a stable conformation. Ran has been structurally characterized in great detail, including different nucleotide states and various protein complexes (2-4).In interphase cells, about 90% of cellular Ran is nuclear, and only a minor proportion is cytosolic (5). The localization of the guanine-nucleotide exchange factor (GEF) RCC1 (Regulator of chromosome condensation 1) at the nuclear chromatin and the RanGAP (RanGTPase-activating protein) at the cytosolic site of the nuclear pore creates a gradient of Ran•GTP in the nucleus and Ran•GDP in the cytosol (6-8).In the nucleus, Ran•GTP binds to exportins such as CRM1 (Chromosome region maintenance 1) to transport cargo proteins containing a nuclear export signal (NES) into the cytosol (3, 9, 10). Ran•GTP, furthermore, binds to Importin-β•cargo complexes to release the cargo in the nucleus (11-15). In the cytosol, the Importin•Ran•GTP complexes, as well as the ternary exportin•Ran•GTP-cargo complexes, dissociate on binding of RanBP1 and subsequent GTP hydrolysis catalyzed by RanGAP (16,17). The Ran transport cycle closes by translocation of Ran•GDP to the nucleus by the nuclear transport factor 2 (NTF2) (4,(17)(18)(19)(20). Many of these Ran interactions also ...

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Section: Discussionmentioning

confidence: 99%

Small GTP-binding protein Ran is regulated by posttranslational lysine acetylation

Boor

Knyphausen

Kuhlmann

et al. 2015

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

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“…Lysine acetylation is a reversible process catalyzed by acetyltransferases and deacetylases (9). To identify the acetyltransferase responsible for TyrRS acetylation, we overexpressed p300/CBP-associated factor (PCAF), Tip60, and GCN5 into HEK293T cells, because PCAF, Tip60, and GCN5 have been shown to respond to oxidative stress (22)(23)(24)(25), and found that the acetylation of TyrRS was elevated only after the ectopic expression of PCAF, not the other acetyltransferases ( Fig.…”

Section: Significancementioning

confidence: 99%

“…Protein acetylation, a posttranslational modification process that has been conserved through evolution, has been extensively investigated in recent years (9)(10)(11)(12). Acetylation regulates diverse cellular processes, including gene silencing (13), oxidative stress (13,14), DNA repair (15), cell survival and migration (16,17), and metabolism (9,18,19).…”

Section: Dna Damage Repairmentioning

confidence: 99%

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Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Cao

Xiao

et al. 2017

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

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Tyrosyl-tRNA synthetase (TyrRS) is well known for its essential aminoacylation function in protein synthesis. Recently, TyrRS has been shown to translocate to the nucleus and protect against DNA damage due to oxidative stress. However, the mechanism of TyrRS nuclear localization has not yet been determined. Herein, we report that TyrRS becomes highly acetylated in response to oxidative stress, which promotes nuclear translocation. Moreover, p300/ CBP-associated factor (PCAF), an acetyltransferase, and sirtuin 1 (SIRT1), a NAD + -dependent deacetylase, regulate the nuclear localization of TyrRS in an acetylation-dependent manner. Oxidative stress increases the level of PCAF and decreases the level of SIRT1 and deacetylase activity, all of which promote the nuclear translocation of hyperacetylated TyrRS. Furthermore, TyrRS is primarily acetylated on the K244 residue near the nuclear localization signal (NLS), and acetylation inhibits the aminoacylation activity of TyrRS. Molecular dynamics simulations have shown that the in silico acetylation of K244 induces conformational changes in TyrRS near the NLS, which may promote the nuclear translocation of acetylated TyrRS. Herein, we show that the acetylated K244 residue of TyrRS protects against DNA damage in mammalian cells and zebrafish by activating DNA repair genes downstream of transcription factor E2F1. Our study reveals a previously unknown mechanism by which acetylation regulates an aminoacyl-tRNA synthetase, thus affecting the repair pathways for damaged DNA.

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“…4). Acl2 transforms citrate into acetylCoA and oxaloacetate; in many organisms, including humans, this pathway may be crucial for cellular acetylCoA balance [41][42][43]. To test for links between acetylCoA metabolism and histone acetylation, we deleted the genes for the mitochondrial citrate exporter (mce1) and ATP-citrate lyase (acl1 (SPBC1703.07) and acl2).…”

Section: Acetyl-coenzyme a Metabolismmentioning

confidence: 99%

Functional and Regulatory Profiling of Energy Metabolism in Fission Yeast

Małecki

Bitton

Rodríguez-López

et al. 2016

Preprint

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Background: The control of energy metabolism is fundamental for cell growth and function and anomalies in it are implicated in complex diseases and ageing. Metabolism in yeast cells can be manipulated by supplying different carbon sources: yeast grown on glucose rapidly proliferates by fermentation, analogous to tumour cells growing by aerobic glycolysis, whereas on non-fermentable carbon sources metabolism shifts towards respiration. Results: We screened deletion libraries of fission yeast to identify over 200 genes required for respiratory growth. Growth media and auxotrophic mutants strongly influenced respiratory metabolism. Most genes uncovered in the mutant screens have not been implicated in respiration in budding yeast. We applied gene-expression profiling approaches to compare steady-state fermentative and respiratory growth and to analyse the dynamic adaptation to respiratory growth. The transcript levels of most genes functioning in energy metabolism pathways are coherently tuned, reflecting anticipated differences in metabolic flows between fermenting and respiring cells. We show that acetyl-CoA synthase, rather than citrate lyase, is essential for acetyl-CoA synthesis in fission yeast. We also investigated the transcriptional response to mitochondrial damage by genetic or chemical perturbations, defining a retrograde response that involves the concerted regulation of distinct groups of nuclear genes that may avert harm from mitochondrial malfunction.

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The growing landscape of lysine acetylation links metabolism and cell signalling

Cited by 1,111 publications

References 169 publications

Small GTP-binding protein Ran is regulated by posttranslational lysine acetylation

Small GTP-binding protein Ran is regulated by posttranslational lysine acetylation

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Functional and Regulatory Profiling of Energy Metabolism in Fission Yeast

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