The SAGA Histone Acetyltransferase Complex Regulates Leucine Uptake through the Agp3 Permease in Fission Yeast

Takahashi, Hidekazu; Sun, Xiaoying; Hamamoto, Makiko; Yashiroda, Yoko; Yoshida, Minoru

doi:10.1074/jbc.m112.411165

Cited by 19 publications

(34 citation statements)

References 39 publications

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“…PGC-1␣ is of particular interest in this context because acetylated PGC-1␣ is unable to promote the expression of genes involved in activating fatty acid oxidation upon exposure of muscle cells to low glucose levels (19). Also, in budding yeast, after acetylation, Ifh1 is unable to activate transcription of ribosomal protein genes (24), and in fission yeast, GCN5 suppresses the expression of amino acid permeases and the cellular uptake of leucine (25). These studies together suggest that GCN5 may inhibit adaptive responses to low nutrient supply and reduce overall rates of protein synthesis and thus could play a role in the net loss of muscle protein triggered by nutrient deprivation.…”

mentioning

confidence: 86%

Muscle Wasting in Fasting Requires Activation of NF-κB and Inhibition of AKT/Mechanistic Target of Rapamycin (mTOR) by the Protein Acetylase, GCN5

Lee

Goldberg

2015

Journal of Biological Chemistry

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NF-B is best known for its pro-inflammatory and anti-apoptotic actions, but in skeletal muscle, NF-B activation is important for atrophy upon denervation or cancer. Here, we show that also upon fasting, NF-B becomes activated in muscle and is critical for the subsequent atrophy. Following food deprivation, the expression and acetylation of the p65 of NF-B on lysine 310 increase markedly in muscles. NF-B inhibition in mouse muscles by overexpression of the IB␣ superrepressor (IB␣-SR) or of p65 mutated at Lys-310 prevented atrophy. Knockdown of GCN5 with shRNA or a dominant-negative GCN5 or overexpression of SIRT1 decreased p65K310 acetylation and muscle wasting upon starvation. In addition to reducing atrogene expression, surprisingly inhibiting NF-B with IB␣-SR or by GCN5 knockdown in these muscles also enhanced AKT and mechanistic target of rapamycin (mTOR) activities, which also contributed to the reduction in atrophy. These new roles of NF-B and GCN5 in regulating muscle proteolysis and AKT/ mTOR signaling suggest novel approaches to combat muscle wasting.

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confidence: 86%

Muscle Wasting in Fasting Requires Activation of NF-κB and Inhibition of AKT/Mechanistic Target of Rapamycin (mTOR) by the Protein Acetylase, GCN5

Lee

Goldberg

2015

Journal of Biological Chemistry

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“…to play a role in mRNA decapping, but was unexpectedly grouped with the DNA damage repair proteins, possibly due to a putative connection to TOP2, which cooperates with Est1 to maintain genomic integrity at the telomere (Germe et al 2009) (Figs 2B, S1 in Supporting Information). The second cluster contains components of the histone acetyltransferase SAGA complex (Gcn5, Ngg1, Arp42), which controls gene transcription but has recently been implicated during ER stress, DNA replication and amino acid uptake (Helmlinger et al 2008;Takahashi et al 2012;Schram et al 2013;Vorobyeva et al 2013). The connection between SAGA and ER stress is probably reflected by the connection between the SAGA subunit Ngg1 and Rav1, which were co-isolated as hits in multiple sensitivity screens in fission yeast (Guo et al 2012;Tay et al 2013).…”

Section: Determination Of a Functional Doxorubicin-and Calcium-resistmentioning

confidence: 99%

Calcium modulation of doxorubicin cytotoxicity in yeast and human cells

et al. 2016

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Doxorubicin is a widely used chemotherapeutic agent, but its utility is limited by cellular resistance and off‐target effects. To understand the molecular mechanisms regulating chemotherapeutic responses to doxorubicin, we previously carried out a genomewide search of doxorubicin‐resistance genes in Schizosaccharomyces pombe fission yeast and showed that these genes are organized into networks that counteract doxorubicin cytotoxicity. Here, we describe the identification of a subgroup of doxorubicin‐resistance genes that, when disrupted, leads to reduced tolerance to exogenous calcium. Unexpectedly, we observed a suppressive effect of calcium on doxorubicin cytotoxicity, where concurrent calcium and doxorubicin treatment resulted in significantly higher cell survival compared with cells treated with doxorubicin alone. Conversely, inhibitors of voltage‐gated calcium channels enhanced doxorubicin cytotoxicity in the mutants. Consistent with these observations in fission yeast, calcium also suppressed doxorubicin cytotoxicity in human breast cancer cells. Further epistasis analyses in yeast showed that this suppression of doxorubicin toxicity by calcium was synergistically dependent on Rav1 and Vph2, two regulators of vacuolar‐ATPase assembly; this suggests potential modulation of the calcium–doxorubicin interaction by fluctuating proton concentrations within the cellular environment. Thus, the modulatory effects of drugs or diet on calcium concentrations should be considered in doxorubicin treatment regimes.

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“…Fission yeast ( Schizosaccharomyces pombe ) Eca39 is a branched-chain amino acid aminotransferase, conserved among eukaryotes, that catalyzes the final step of the synthesis of the branched-chain amino acids isoleucine (Ile), leucine (Leu), and valine (Val). The auxotrophic mutant eca39 Δ was unable to grow on minimal medium containing glutamate (EMM [Glu]) even when supplemented with Ile, Leu, and Val, because the uptake of these amino acids was suppressed in the presence of the high-quality nitrogen source Glu 3 . In previous work, however, we discovered a peculiar phenotype of adaptation to poor nitrogen sources.…”

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confidence: 99%

Identification of novel secreted fatty acids that regulate nitrogen catabolite repression in fission yeast

Sun

Hirai

Ueki

et al. 2016

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Uptake of poor nitrogen sources such as branched-chain amino acids is repressed in the presence of high-quality nitrogen sources such as NH4+ and glutamate (Glu), which is called nitrogen catabolite repression. Amino acid auxotrophic mutants of the fission yeast Schizosaccharomyces pombe were unable to grow on minimal medium containing NH4Cl or Glu even when adequate amounts of required amino acids were supplied. However, growth of these mutant cells was recovered in the vicinity of colonies of the prototrophic strain, suggesting that the prototrophic cells secrete some substances that can restore uptake of amino acids by an unknown mechanism. We identified the novel fatty acids, 10(R)-acetoxy-8(Z)-octadecenoic acid and 10(R)-hydroxy-8(Z)-octadecenoic acid, as secreted active substances, referred to as Nitrogen Signaling Factors (NSFs). Synthetic NSFs were also able to shift nitrogen source utilization from high-quality to poor nitrogen sources to allow adaptive growth of the fission yeast amino acid auxotrophic mutants in the presence of high-quality nitrogen sources. Finally, we demonstrated that the Agp3 amino acid transporter was involved in the adaptive growth. The data highlight a novel intra-species communication system for adaptation to environmental nutritional conditions in fission yeast.

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The SAGA Histone Acetyltransferase Complex Regulates Leucine Uptake through the Agp3 Permease in Fission Yeast

Cited by 19 publications

References 39 publications

Muscle Wasting in Fasting Requires Activation of NF-κB and Inhibition of AKT/Mechanistic Target of Rapamycin (mTOR) by the Protein Acetylase, GCN5

Muscle Wasting in Fasting Requires Activation of NF-κB and Inhibition of AKT/Mechanistic Target of Rapamycin (mTOR) by the Protein Acetylase, GCN5

Calcium modulation of doxorubicin cytotoxicity in yeast and human cells

Identification of novel secreted fatty acids that regulate nitrogen catabolite repression in fission yeast

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