title: Proteasome activity is required for the stage-specific transformation of a protozoan parasite.
abstract: A prominent feature of the life cycle of intracellular parasites is the profound morphological changes they undergo during development in the vertebrate and invertebrate hosts. In eukaryotic cells, most cytoplasmic proteins are degraded in proteasomes. Here, we show that the transformation in axenic medium of trypomastigotes of Trypanosoma cruzi into amastigote-like organisms, and the intracellular development of the parasite from amastigotes into trypomastigotes, are prevented by lactacystin, or by a peptide aldehyde that inhibits proteasome function. Clasto-lactacystin, an inactive analogue of lactacystin, and cell-permeant peptide aldehyde inhibitors of T. cruzi cysteine proteinases have no effect. We have also identified the 20S proteasomes from T. cruzi as a target of lactacystin in vivo. Our results document the essential role of proteasomes in the stage-specific transformation of a protozoan.
authors.affiliation: Michael Heidelberger Division of Immunology, Department of Pathology, New York, University Medical Center, New York 10016, USA.
authors.forename: J
authors.initials: J
authors.lastname: González
authors.forename: F J
authors.initials: FJ
authors.lastname: Ramalho-Pinto
authors.forename: U
authors.initials: U
authors.lastname: Frevert
authors.forename: J
authors.initials: J
authors.lastname: Ghiso
authors.forename: S
authors.initials: S
authors.lastname: Tomlinson
authors.forename: J
authors.initials: J
authors.lastname: Scharfstein
authors.forename: E J
authors.initials: EJ
authors.lastname: Corey
authors.forename: V
authors.initials: V
authors.lastname: Nussenzweig
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000648:ultrastructure; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D009097:Multienzyme Complexes / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000648:ultrastructure; D046988:Proteasome Endopeptidase Complex; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D009097:Multienzyme Complexes; C067713:lactacystin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine