title: Primary cilium suppression by SREBP1c involves distortion of vesicular trafficking by PLA2G3.
abstract: Distortion of primary cilium formation is increasingly recognized as a key event in many human pathologies. One of the underlying mechanisms involves aberrant activation of the lipogenic transcription factor sterol regulatory element-binding protein 1c (SREBP1c), as observed in cancer cells. To gain more insight into the molecular pathways by which SREBP1c suppresses primary ciliogenesis, we searched for overlap between known ciliogenesis regulators and targets of SREBP1. One of the candidate genes that was consistently up-regulated in cellular models of SREBP1c-induced cilium repression was phospholipase A2 group III (PLA2G3), a phospholipase that hydrolyzes the sn-2 position of glycerophospholipids. Use of RNA interference and a chemical inhibitor of PLA2G3 rescued SREBP1c-induced cilium repression. Cilium repression by SREBP1c and PLA2G3 involved alterations in endosomal recycling and vesicular transport toward the cilium, as revealed by aberrant transferrin and Rab11 localization, and was largely mediated by an increase in lysophosphatidylcholine and lysophosphatidylethanolamine levels. Together these findings indicate that aberrant activation of SREBP1c suppresses primary ciliogenesis by PLA2G3-mediated distortion of vesicular trafficking and suggest that PLA2G3 is a novel potential target to normalize ciliogenesis in SREBP1c-overexpressing cells, including cancer cells.
authors.affiliation: Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven-University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Hannah Laura
authors.initials: HL
authors.lastname: Gijs
authors.affiliation: Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven-University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Willemarck
authors.affiliation: Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven-University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Vanderhoydonc
authors.affiliation: Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven-University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Niamat Ali
authors.initials: NA
authors.lastname: Khan
authors.affiliation: Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven-University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Jonas
authors.initials: J
authors.lastname: Dehairs
authors.affiliation: Laboratory of Protein Phosphorylation and Proteomics, KU Leuven-University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Rita
authors.initials: R
authors.lastname: Derua
authors.affiliation: Laboratory of Protein Phosphorylation and Proteomics, KU Leuven-University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Etienne
authors.initials: E
authors.lastname: Waelkens
authors.affiliation: Department of Advanced Science for Biomolecules, Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Taketomi
authors.affiliation: Department of Advanced Science for Biomolecules, Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, KU Leuven-University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
authors.affiliation: Laboratory for Membrane Trafficking, Center for the Biology of Disease and Department of Human Genetics, KU Leuven-University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Annaert
authors.affiliation: Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven-University of Leuven, B-3000 Leuven, Belgium johan.swinnen@med.kuleuven.be.
authors.forename: Johannes V
authors.initials: JV
authors.lastname: Swinnen
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism / Q000502:physiology*; D004285:Dogs; D005260:Female; D054520:Group III Phospholipases A2 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D021381:Protein Transport; D016415:Sequence Alignment; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology*; D034421:Sus scrofa; D022161:Transport Vesicles / Q000502:physiology*
chemical_list: D051780:Sterol Regulatory Element Binding Protein 1; D054520:Group III Phospholipases A2; C484163:PLA2G3 protein, human