P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation

Matteo Savoia, Chiara Cencioni, Mattia Mori, Sandra Atlante, Germana Zaccagnini, Paolo Devanna, Lucia Di Marcotullio, Bruno Botta, Fabio Martelli, Andreas M Zeiher, Alfredo Pontecorvi, Antonella Farsetti, Francesco Spallotta, Carlo Gaetano

Research output: Contribution to journalArticle

Abstract

The epigenetic enzyme p300/CBP-associated factor (PCAF) belongs to the GCN5-related N-acetyltransferase (GNAT) family together with GCN5. Although its transcriptional and post-translational function is well characterized, little is known about its properties as regulator of cell metabolism. Here, we report the mitochondrial localization of PCAF conferred by an 85 aa mitochondrial targeting sequence (MTS) at the N terminus region of the protein. In mitochondria, one of the PCAF targets is the isocitrate dehydrogenase 2 (IDH2) acetylated at lysine 180. This PCAF-regulated post-translational modification might reduce IDH2 affinity for isocitrate as a result of a conformational shift involving predictively the tyrosine at position 179. Site-directed mutagenesis and functional studies indicate that PCAF regulates IDH2, acting at dual level during myoblast differentiation: at a transcriptional level together with MyoD, and at a post-translational level by direct modification of lysine acetylation in mitochondria. The latter event determines a decrease in IDH2 function with negative consequences on muscle fiber formation in C2C12 cells. Indeed, a MTS-deprived PCAF does not localize into mitochondria, remains enriched into the nucleus, and contributes to a significant increase of muscle-specific gene expression enhancing muscle differentiation. The role of PCAF in mitochondria is a novel finding shedding light on metabolic processes relevant to early muscle precursor differentiation.-Savoia, M., Cencioni, C., Mori, M., Atlante, S., Zaccagnini, G., Devanna, P., Di Marcotullio, L., Botta, B., Martelli, F., Zeiher, A. M., Pontecorvi, A., Farsetti, A., Spallotta, F., Gaetano, C. P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation.

Original languageEnglish
Pages (from-to)fj201800788R
JournalFASEB Journal
DOIs
Publication statusE-pub ahead of print - Dec 10 2018

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Isocitrate Dehydrogenase
Transcription
Muscle
Muscles
Mitochondria
Lysine
Morus
Acetylation
Mutagenesis
Acetyltransferases
p300-CBP-associated factor
Myoblasts
Post Translational Protein Processing
Site-Directed Mutagenesis
Metabolism
Epigenomics
Gene expression
Tyrosine
Gene Expression
Fibers

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Savoia, M., Cencioni, C., Mori, M., Atlante, S., Zaccagnini, G., Devanna, P., ... Gaetano, C. (2018). P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation. FASEB Journal, fj201800788R. https://doi.org/10.1096/fj.201800788R

P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation. / Savoia, Matteo; Cencioni, Chiara; Mori, Mattia; Atlante, Sandra; Zaccagnini, Germana; Devanna, Paolo; Di Marcotullio, Lucia; Botta, Bruno; Martelli, Fabio; Zeiher, Andreas M; Pontecorvi, Alfredo; Farsetti, Antonella; Spallotta, Francesco; Gaetano, Carlo.

In: FASEB Journal, 10.12.2018, p. fj201800788R.

Research output: Contribution to journalArticle

Savoia, M, Cencioni, C, Mori, M, Atlante, S, Zaccagnini, G, Devanna, P, Di Marcotullio, L, Botta, B, Martelli, F, Zeiher, AM, Pontecorvi, A, Farsetti, A, Spallotta, F & Gaetano, C 2018, 'P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation', FASEB Journal, pp. fj201800788R. https://doi.org/10.1096/fj.201800788R
Savoia, Matteo ; Cencioni, Chiara ; Mori, Mattia ; Atlante, Sandra ; Zaccagnini, Germana ; Devanna, Paolo ; Di Marcotullio, Lucia ; Botta, Bruno ; Martelli, Fabio ; Zeiher, Andreas M ; Pontecorvi, Alfredo ; Farsetti, Antonella ; Spallotta, Francesco ; Gaetano, Carlo. / P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation. In: FASEB Journal. 2018 ; pp. fj201800788R.
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abstract = "The epigenetic enzyme p300/CBP-associated factor (PCAF) belongs to the GCN5-related N-acetyltransferase (GNAT) family together with GCN5. Although its transcriptional and post-translational function is well characterized, little is known about its properties as regulator of cell metabolism. Here, we report the mitochondrial localization of PCAF conferred by an 85 aa mitochondrial targeting sequence (MTS) at the N terminus region of the protein. In mitochondria, one of the PCAF targets is the isocitrate dehydrogenase 2 (IDH2) acetylated at lysine 180. This PCAF-regulated post-translational modification might reduce IDH2 affinity for isocitrate as a result of a conformational shift involving predictively the tyrosine at position 179. Site-directed mutagenesis and functional studies indicate that PCAF regulates IDH2, acting at dual level during myoblast differentiation: at a transcriptional level together with MyoD, and at a post-translational level by direct modification of lysine acetylation in mitochondria. The latter event determines a decrease in IDH2 function with negative consequences on muscle fiber formation in C2C12 cells. Indeed, a MTS-deprived PCAF does not localize into mitochondria, remains enriched into the nucleus, and contributes to a significant increase of muscle-specific gene expression enhancing muscle differentiation. The role of PCAF in mitochondria is a novel finding shedding light on metabolic processes relevant to early muscle precursor differentiation.-Savoia, M., Cencioni, C., Mori, M., Atlante, S., Zaccagnini, G., Devanna, P., Di Marcotullio, L., Botta, B., Martelli, F., Zeiher, A. M., Pontecorvi, A., Farsetti, A., Spallotta, F., Gaetano, C. P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation.",
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T1 - P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation

AU - Savoia, Matteo

AU - Cencioni, Chiara

AU - Mori, Mattia

AU - Atlante, Sandra

AU - Zaccagnini, Germana

AU - Devanna, Paolo

AU - Di Marcotullio, Lucia

AU - Botta, Bruno

AU - Martelli, Fabio

AU - Zeiher, Andreas M

AU - Pontecorvi, Alfredo

AU - Farsetti, Antonella

AU - Spallotta, Francesco

AU - Gaetano, Carlo

PY - 2018/12/10

Y1 - 2018/12/10

N2 - The epigenetic enzyme p300/CBP-associated factor (PCAF) belongs to the GCN5-related N-acetyltransferase (GNAT) family together with GCN5. Although its transcriptional and post-translational function is well characterized, little is known about its properties as regulator of cell metabolism. Here, we report the mitochondrial localization of PCAF conferred by an 85 aa mitochondrial targeting sequence (MTS) at the N terminus region of the protein. In mitochondria, one of the PCAF targets is the isocitrate dehydrogenase 2 (IDH2) acetylated at lysine 180. This PCAF-regulated post-translational modification might reduce IDH2 affinity for isocitrate as a result of a conformational shift involving predictively the tyrosine at position 179. Site-directed mutagenesis and functional studies indicate that PCAF regulates IDH2, acting at dual level during myoblast differentiation: at a transcriptional level together with MyoD, and at a post-translational level by direct modification of lysine acetylation in mitochondria. The latter event determines a decrease in IDH2 function with negative consequences on muscle fiber formation in C2C12 cells. Indeed, a MTS-deprived PCAF does not localize into mitochondria, remains enriched into the nucleus, and contributes to a significant increase of muscle-specific gene expression enhancing muscle differentiation. The role of PCAF in mitochondria is a novel finding shedding light on metabolic processes relevant to early muscle precursor differentiation.-Savoia, M., Cencioni, C., Mori, M., Atlante, S., Zaccagnini, G., Devanna, P., Di Marcotullio, L., Botta, B., Martelli, F., Zeiher, A. M., Pontecorvi, A., Farsetti, A., Spallotta, F., Gaetano, C. P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation.

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DO - 10.1096/fj.201800788R

M3 - Article

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