2. Academic Validation
  3. FIT2 is an acyl-coenzyme A diphosphatase crucial for endoplasmic reticulum homeostasis

FIT2 is an acyl-coenzyme A diphosphatase crucial for endoplasmic reticulum homeostasis

  • J Cell Biol. 2020 Oct 5;219(10):e202006111. doi: 10.1083/jcb.202006111.
Michel Becuwe 1 2 3,  Laura M Bond 1 2 3,  Antonio F M Pinto 4,  Sebastian Boland 1 2 3,  Niklas Mejhert 1 2 3,  Shane D Elliott 1 2 3 5,  Marcelo Cicconet 6,  Morven M Graham 7,  Xinran N Liu 7,  Olga Ilkayeva 8,  Alan Saghatelian 4,  Tobias C Walther 1 2 3 5,  Robert V Farese Jr. 1 2 3
Affiliations

Affiliations

  • 1 Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA.
  • 2 Department of Cell Biology, Harvard Medical School, Boston, MA.
  • 3 Broad Institute of MIT and Harvard, Cambridge, MA.
  • 4 Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA.
  • 5 Howard Hughes Medical Institute, Boston, MA.
  • 6 Image and Data Analysis Core, Harvard Medical School, Boston, MA.
  • 7 Center for Cellular and Molecular Imaging, Department of Cell Biology, Yale School of Medicine, New Haven, CT.
  • 8 Departments of Medicine and Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, NC.
PMID: 32915949 DOI: 10.1083/jcb.202006111
Abstract

The endoplasmic reticulum is a cellular hub of lipid metabolism, coordinating lipid synthesis with continuous changes in metabolic flux. Maintaining ER lipid homeostasis despite these fluctuations is crucial to cell function and viability. Here, we identify a novel mechanism that is crucial for normal ER lipid metabolism and protects the ER from dysfunction. We identify the molecular function of the evolutionarily conserved ER protein FIT2 as a fatty acyl-coenzyme A (CoA) diphosphatase that hydrolyzes fatty acyl-CoA to yield acyl 4'-phosphopantetheine. This activity of FIT2, which is predicted to be active in the ER lumen, is required in yeast and mammalian cells for maintaining ER structure, protecting against ER stress, and enabling normal lipid storage in lipid droplets. Our findings thus solve the long-standing mystery of the molecular function of FIT2 and highlight the maintenance of optimal fatty acyl-CoA levels as key to ER homeostasis.

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