Metabolic coessentiality mapping identifies C12orf49 as a regulator of SREBP processing and cholesterol metabolism

Nature Metabolism
Erol C BayraktarKıvanç Birsoy

Abstract

Coessentiality mapping has been useful to systematically cluster genes into biological pathways and identify gene functions1-3. Here, using the debiased sparse partial correlation (DSPC) method3, we construct a functional coessentiality map for cellular metabolic processes across human cancer cell lines. This analysis reveals 35 modules associated with known metabolic pathways and further assigns metabolic functions to unknown genes. In particular, we identify C12orf49 as an essential regulator of cholesterol and fatty acid metabolism in mammalian cells. Mechanistically, C12orf49 localizes to the Golgi, binds membrane-bound transcription factor peptidase, site 1 (MBTPS1, site 1 protease) and is necessary for the cleavage of its substrates, including sterol regulatory element binding protein (SREBP) transcription factors. This function depends on the evolutionarily conserved uncharacterized domain (DUF2054) and promotes cell proliferation under cholesterol depletion. Notably, c12orf49 depletion in zebrafish blocks dietary lipid clearance in vivo, mimicking the phenotype of mbtps1 mutants. Finally, in an electronic health record (EHR)-linked DNA biobank, C12orf49 is associated with hyperlipidaemia through phenome analysis. Altoge...Continue Reading

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Citations

Jul 23, 2020·Nature Metabolism·Enrico Girardi, Giulio Superti-Furga
Dec 18, 2020·Life Science Alliance·David R AmiciMarc L Mendillo
Feb 15, 2021·Experimental Cell Research·Yusuke SekineShiori Sekine
Jun 3, 2021·International Journal of Molecular Sciences·Mayra ColardoMarco Segatto

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Datasets Mentioned

BETA
MDA-MB-435
GM130
PXD018368

Methods Mentioned

BETA
nuclear translocation
immunoprecipitation
PCR
transfection
Protein Assay
flow cytometry
Assay

Software Mentioned

Clustal W
DSPC
pcor
DNASTAR
Skyline
ppcor
FlowJo
MassHunter Qualitative Analysis
GeneNetWeaver
PrediXcan

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