title: The GARP complex is required for cellular sphingolipid homeostasis.
abstract: Sphingolipids are abundant membrane components and important signaling molecules in eukaryotic cells. Their levels and localization are tightly regulated. However, the mechanisms underlying this regulation remain largely unknown. In this study, we identify the Golgi-associated retrograde protein (GARP) complex, which functions in endosome-to-Golgi retrograde vesicular transport, as a critical player in sphingolipid homeostasis. GARP deficiency leads to accumulation of sphingolipid synthesis intermediates, changes in sterol distribution, and lysosomal dysfunction. A GARP complex mutation analogous to a VPS53 allele causing progressive cerebello-cerebral atrophy type 2 (PCCA2) in humans exhibits similar, albeit weaker, phenotypes in yeast, providing mechanistic insights into disease pathogenesis. Inhibition of the first step of de novo sphingolipid synthesis is sufficient to mitigate many of the phenotypes of GARP-deficient yeast or mammalian cells. Together, these data show that GARP is essential for cellular sphingolipid homeostasis and suggest a therapeutic strategy for the treatment of PCCA2.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.|Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Florian
authors.initials: F
authors.lastname: Fröhlich
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.|Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Constance
authors.initials: C
authors.lastname: Petit
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.|Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Nora
authors.initials: N
authors.lastname: Kory
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.|Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Romain
authors.initials: R
authors.lastname: Christiano
authors.affiliation: Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Hans-Kristian
authors.initials: HK
authors.lastname: Hannibal-Bach
authors.affiliation: Center for Cellular and Molecular Imaging, Yale School of Medicine, New Haven, United States.
authors.forename: Morven
authors.initials: M
authors.lastname: Graham
authors.affiliation: Center for Cellular and Molecular Imaging, Yale School of Medicine, New Haven, United States.|Department of Cell Biology, Yale School of Medicine, New Haven, United States.
authors.forename: Xinran
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Christer S
authors.initials: CS
authors.lastname: Ejsing
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.|Department of Cell Biology, Harvard Medical School, Boston, United States.|Broad Institute, Cambridge, United States.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.|Department of Cell Biology, Harvard Medical School, Boston, United States.|Broad Institute, Cambridge, United States.|Howard Hughes Medical Institute, Harvard T.H. Chan School of Public Health, Boston, United States.
authors.forename: Tobias C
authors.initials: TC
authors.lastname: Walther
mesh_terms: D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism*
chemical_list: C087215:LRRC32 protein, human; D008565:Membrane Proteins; D013107:Sphingolipids
keywords: GARP complex; PCCA2; S. cerevisiae; cell biology; homeostasis; human; neurodegeneration; retrograde endosome to Golgi transport; sphingolipid metabolism