title: HK2 Recruitment to Phospho-BAD Prevents Its Degradation, Promoting Warburg Glycolysis by Theileria-Transformed Leukocytes.
abstract: Theileria annulata infects bovine leukocytes, transforming them into invasive, cancer-like cells that cause the widespread disease called tropical theileriosis. We report that in Theileria-transformed leukocytes hexokinase-2 (HK2) binds to B cell lymphoma-2-associated death promoter (BAD) only when serine (S) 155 in BAD is phosphorylated. We show that HK2 recruitment to BAD is abolished by a cell-penetrating peptide that acts as a nonphosphorylatable BAD substrate that inhibits endogenous S155 phosphorylation, leading to complex dissociation and ubiquitination and degradation of HK2 by the proteasome. As HK2 is a critical enzyme involved in Warburg glycolysis, its loss forces Theileria-transformed macrophages to switch back to HK1-dependent oxidative glycolysis that down-regulates macrophage proliferation only when they are growing on glucose. When growing on galactose, degradation of HK2 has no effect on Theileria-infected leukocyte proliferation, because metabolism of this sugar is independent of hexokinases. Thus, targeted disruption of the phosphorylation-dependent HK2/BAD complex may represent a novel approach to control Theileria-transformed leukocyte proliferation.
authors.affiliation: Inserm U1016, CNRS UMR8104, Cochin Institute , Paris 75014 France.|Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médecine, Université Paris Descartes - Sorbonne Paris Cité , Paris 75014, France.
authors.forename: Malak
authors.initials: M
authors.lastname: Haidar
authors.affiliation: Inserm U1016, CNRS UMR8104, Cochin Institute , Paris 75014 France.|Laboratoire de Mitochondries, Bioénergétique, Métabolisme et Signalisation, Faculté de Médicine, Université Paris Descartes - Sorbonne Paris Cité , Paris 75014, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Lombès
authors.affiliation: Inserm U1016, CNRS UMR8104, Cochin Institute , Paris 75014 France.|Laboratoire de Mitochondries, Bioénergétique, Métabolisme et Signalisation, Faculté de Médicine, Université Paris Descartes - Sorbonne Paris Cité , Paris 75014, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bouillaud
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Eileen J
authors.initials: EJ
authors.lastname: Kennedy
authors.affiliation: Inserm U1016, CNRS UMR8104, Cochin Institute , Paris 75014 France.|Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médecine, Université Paris Descartes - Sorbonne Paris Cité , Paris 75014, France.
authors.forename: Gordon
authors.identifier: 0000-0001-6600-6286
authors.initials: G
authors.lastname: Langsley
mesh_terms: D000818:Animals; D002417:Cattle; D002418:Cattle Diseases / Q000378:metabolism / Q000469:parasitology*; D049109:Cell Proliferation; D057846:Cell-Penetrating Peptides / Q000494:pharmacology; D006019:Glycolysis; D006593:Hexokinase / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism / Q000469:parasitology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D012694:Serine / Q000378:metabolism; D016796:Theileria annulata / Q000472:pathogenicity*; D013801:Theileriasis / Q000378:metabolism* / Q000469:parasitology; D051025:bcl-Associated Death Protein / Q000235:genetics*
chemical_list: D057846:Cell-Penetrating Peptides; D051025:bcl-Associated Death Protein; D012694:Serine; D006593:Hexokinase
keywords: BAD; Theileria; Warburg; glycolysis; hexokinase; oxidative phosphorylation