title: Inositol phosphate pathway controls transcription of telomeric expression sites in trypanosomes.
abstract: African trypanosomes evade clearance by host antibodies by periodically changing their variant surface glycoprotein (VSG) coat. They transcribe only one VSG gene at a time from 1 of about 20 telomeric expression sites (ESs). They undergo antigenic variation by switching transcription between telomeric ESs or by recombination of the VSG gene expressed. We show that the inositol phosphate (IP) pathway controls transcription of telomeric ESs and VSG antigenic switching in Trypanosoma brucei. Conditional knockdown of phosphatidylinositol 5-kinase (TbPIP5K) or phosphatidylinositol 5-phosphatase (TbPIP5Pase) or overexpression of phospholipase C (TbPLC) derepresses numerous silent ESs in T. brucei bloodstream forms. The derepression is specific to telomeric ESs, and it coincides with an increase in the number of colocalizing telomeric and RNA polymerase I foci in the nucleus. Monoallelic VSG transcription resumes after reexpression of TbPIP5K; however, most of the resultant cells switched the VSG gene expressed. TbPIP5K, TbPLC, their substrates, and products localize to the plasma membrane, whereas TbPIP5Pase localizes to the nucleus proximal to telomeres. TbPIP5Pase associates with repressor/activator protein 1 (TbRAP1), and their telomeric silencing function is altered by TbPIP5K knockdown. These results show that specific steps in the IP pathway control ES transcription and antigenic switching in T. brucei by epigenetic regulation of telomere silencing.
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109; and.
authors.forename: Igor
authors.initials: I
authors.lastname: Cestari
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109; and Department of Global Health, University of Washington, Seattle, WA 98195 ken.stuart@seattlebiomed.org.
authors.forename: Ken
authors.initials: K
authors.lastname: Stuart
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000940:Antigenic Variation / Q000235:genetics; D055785:Gene Knockdown Techniques; D017125:Genes, Protozoan; D005812:Genes, Switch; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008969:Molecular Sequence Data; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D016615:Telomere / Q000235:genetics*; D014158:Transcription, Genetic; D014346:Trypanosoma brucei brucei / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000235:genetics / Q000276:immunology; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D007295:Inositol Phosphates; D010744:Phosphoric Monoester Hydrolases; D017853:Phosphotransferases (Alcohol Group Acceptor); D015800:Protozoan Proteins; D014643:Variant Surface Glycoproteins, Trypanosoma; D000099182:Phosphoinositide 5-Phosphatases; C020077:1-phosphatidylinositol-4-phosphate 5-kinase
keywords: antigenic variation; inositol phosphates; telomere silencing; transcription; trypanosomes