PXD043054

PXD043054 is an original dataset announced via ProteomeXchange.

Title	Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism
Description	Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally down-regulated protein 8, to target proteins, with yet-unknown consequences. Here we show in mice that neddylation in liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver (either pharmacologically or genetically) reduces gluconeogenic capacity and the hyperglycemic actions of counterregulatory hormones (glucagon, adrenaline and glucocorticoids). Further, people with obesity and type 2 diabetes (compared to people with obesity and normoglycemia) display elevated hepatic neddylation levels that correlate positively with fasting glucose levels. Mechanistically, we determined that fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues—K278, K342 and K387. PCK1 is a key control point for gluconeogenesis regulation that can be post-translationally modified by acetylation and phosphorylation, but to date no modifications are known to affect its gluconeogenic capacity. Of note, we find that mutating the three PCK1 lysines that are neddylated reduces its gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely-tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:05:51.121.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Susana Bravo
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	neddylated lysine
Instrument	TripleTOF 6600

Revision	Datetime	Status	ChangeLog Entry
0	2023-06-16 05:57:52	ID requested
1	2023-10-08 14:22:05	announced
⏵ 2	2023-11-14 09:05:52	announced	2023-11-14: Updated project metadata.

Gonzalez-Rellan MJ, Fern, á, ndez U, Parracho T, Novoa E, Fondevila MF, da Silva Lima N, Ramos L, Rodr, í, guez A, Serrano-Maci, á M, Perez-Mejias G, Chantada-Vazquez P, Riobello C, Veyrat-Durebex C, Tovar S, Coppari R, Woodhoo A, Schwaninger M, Prevot V, Delgado TC, Lopez M, Diaz-Quintana A, Dieguez C, Guallar D, Fr, ü, hbeck G, Diaz-Moreno I, Bravo SB, Martinez-Chantar ML, Nogueiras R, Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism. Cell Metab, 35(9):1630-1645.e5(2023) [pubmed]

submitter keyword: PCK1,neddylation, glucose

Susana Belén Bravo López
contact affiliation	Instituto de Investigaciones Sanitarias de Santiago de Compostela
contact email	sbbravo@gmail.com
lab head
Susana Bravo
contact affiliation	FIDIS
contact email	sbbravo@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD043054
     1. Label: PRIDE project
     2. Name: Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism