Dataset Information

Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity.

ABSTRACT: Data from ProteomeXchange, PXD ID: PXD001447. Experiment: SIRT4_MITO_MOCK1, file: SIRT4_MITO_MOCK1_05.mzml. Published as part of Cell. 2014 Dec 18;159(7):1615-25 . From the Abstract: {{i}} ... Here, we establish SIRT4 as a cellular lipoamidase that regulates the pyruvate dehydrogenase complex (PDH). Importantly, SIRT4 catalytic efficiency for lipoyl- and biotinyl-lysine modifications is superior to its deacetylation activity. PDH, which converts pyruvate to acetyl-CoA, has been known to be primarily regulated by phosphorylation of its E1 component. We determine that SIRT4 enzymatically hydrolyzes the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase (DLAT), diminishing PDH activity ... {{/i}}

INSTRUMENT(S): Instrument

ORGANISM(S): Homo_sapiens_viruses, Human

DISEASE(S): Not Available

SUBMITTER: Mathias RA, et al.

PROVIDER: GPM32320006423 | GPMDB |

REPOSITORIES: GPMDB

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Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity.

Mathias Rommel A RA Greco Todd M TM Oberstein Adam A Budayeva Hanna G HG Chakrabarti Rumela R Rowland Elizabeth A EA Kang Yibin Y Shenk Thomas T Cristea Ileana M IM

Cell 20141201 7

Sirtuins (SIRTs) are critical enzymes that govern genome regulation, metabolism, and aging. Despite conserved deacetylase domains, mitochondrial SIRT4 and SIRT5 have little to no deacetylase activity, and a robust catalytic activity for SIRT4 has been elusive. Here, we establish SIRT4 as a cellular lipoamidase that regulates the pyruvate dehydrogenase complex (PDH). Importantly, SIRT4 catalytic efficiency for lipoyl- and biotinyl-lysine modifications is superior to its deacetylation activity. PD ...[more]

PMID: 25525879

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Project description:Purpose: CREB (cAMP response element binding protein) is a transcription factor that is critical for learning and memory. The activity of CREB is mediated through its post-translational modifications (PTMs); specifically, phosphorylation at serine 133 and glycosylation at serine 40. In this study, we used RNA-Seq and weighted gene network coexpression analysis (WGCNA) to determine the CREB-mediated transcriptional programmes that are regulated by phosphorylation at serine 133 and glycosylation at serine 40 through the use of various PTM-deficient CREB mutants. Methods: The mRNA profiles of E16.5 Creb1-/- mouse cortical neurons expressing GFP, WT CREB, S40A-CREB, S133A-CREB, and S40A-S133A-CREB were generated by deep sequencing, in triplicate, using Illumina HiSeq 2500. The sequence reads that passed quality filters were analyzed using Bowtie, aligned using TopHat, and quantified using Cufflinks in Galaxy. Results: Through differential expression analysis with glycosylation-deficient (S40A) and phosphorylation-deficient (S133A) CREB mutants, we show that CREB O-GlcNAcylation is important for neuronal activity and excitability, while phosphorylation at serine 133 regulates the expression of genes involved in neuronal differentiation. Furthermore, many of the S40A and S133A differentially-expressed genes were directly bound by (1) CREB and its co-activators, CREB-binding protein and p300, (2) activating histone modifications, (3) OGT and O-GlcNAc, and (4) Tet1, an critical regulator of neuronal activity and differentiation. Finally, we observed a positive correlation between S40A and activity- and excitotoxicity-related gene networks and a negative correlation between S133A and neuronal differentiation and amino and fatty acid metabolism-related gene networks. This study demonstrates that CREB O-GlcNAcylation at serine 40 and phosphorylation mediate mutually exclusive gene networks. Together, O-GlcNAc and phosphorylation impart a TF code, which CREB must integrate and decode to modulate neuronal activity, differentiation, and metabolism.

Dataset Information

Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity.

Publications

Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity.

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