title: The bacterial-like HslVU protease complex subunits are involved in the control of different cell cycle events in trypanosomatids.
abstract: The trypanosomatid parasites Leishmania and Trypanosoma are responsible for the most important WHO-designated neglected tropical diseases, for which the need for cost-effective new drugs is urgent. In addition to the classical eukaryotic 20S and 26S proteasomes, these unconventional eukaryotes possess a bacterial-like protease complex, HslVU, made of proteolytic (HslV) and regulatory (HslU) subunits. In trypanosomatids, two paralogous genes are co-expressed: HslU1 and HslU2. Conflicting reports have been published with respect to subcellular localization, functional redundancy and putative roles of the different subunits of this complex in trypanosomatids. Here, we definitively established the mitochondrial localization of HslVU in L. major procyclic promastigotes and of HslV in T. brucei bloodstream trypomastigotes, the latter being the form responsible for the disease in the mammalian host. Moreover, our data demonstrate for the first time the essential nature of HslVU in the bloodstream trypomastigotes of T. brucei, in spite of mitochondrial repression at this stage. Interestingly, our work also allows distinguishing a specific role for the different members of the complex, as HslV and HslU1 appear to be involved in the control of different cell cycle events. Finally, these data validate HslVU as a promising drug target against these parasitic diseases of wide medical and economical importance.
authors.affiliation: University of Montpellier 1, Faculty of Medicine, Laboratory of Parasitology-Mycology, Montpellier, France; CNRS UMR5290/IRD 224/University Montpellier 1&2 ("MIVEGEC"), Montpellier, France.
authors.forename: Diane-Ethna
authors.initials: DE
authors.lastname: Mbang-Benet
authors.affiliation: University of Montpellier 1, Faculty of Medicine, Laboratory of Parasitology-Mycology, Montpellier, France; CNRS UMR5290/IRD 224/University Montpellier 1&2 ("MIVEGEC"), Montpellier, France; Centre Hospitalier Régional Universitaire of Montpellier, Montpellier, France.
authors.forename: Yvon
authors.initials: Y
authors.lastname: Sterkers
authors.affiliation: University of Montpellier 1, Faculty of Medicine, Laboratory of Parasitology-Mycology, Montpellier, France; CNRS UMR5290/IRD 224/University Montpellier 1&2 ("MIVEGEC"), Montpellier, France; Centre Hospitalier Régional Universitaire of Montpellier, Montpellier, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Morelle
authors.affiliation: CNRS UMR5237/University Montpellier 1 & 2 ("CRBM"), Montpellier, France.
authors.forename: Ndeye-Mathy
authors.initials: NM
authors.lastname: Kebe
authors.affiliation: CNRS UMR5290/IRD 224/University Montpellier 1&2 ("MIVEGEC"), Montpellier, France.
authors.forename: Lucien
authors.initials: L
authors.lastname: Crobu
authors.affiliation: Centre Hospitalier Régional Universitaire of Montpellier, Montpellier, France; University Montpellier 1, Faculty of Medicine, Laboratory of Immunology, Montpellier, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Portalès
authors.affiliation: CNRS UMR5237/University Montpellier 1 & 2 ("CRBM"), Montpellier, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Coux
authors.affiliation: CNRS UMR5247/University Montpellier 1&2 ("Institut des Biomolécules Max Mousseron"), Montpellier, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Hernandez
authors.affiliation: University of Montpellier 1, Faculty of Medicine, Laboratory of Parasitology-Mycology, Montpellier, France; CNRS UMR5290/IRD 224/University Montpellier 1&2 ("MIVEGEC"), Montpellier, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Meghamla
authors.affiliation: University of Montpellier 1, Faculty of Medicine, Laboratory of Parasitology-Mycology, Montpellier, France; CNRS UMR5290/IRD 224/University Montpellier 1&2 ("MIVEGEC"), Montpellier, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Pagès
authors.affiliation: University of Montpellier 1, Faculty of Medicine, Laboratory of Parasitology-Mycology, Montpellier, France; CNRS UMR5290/IRD 224/University Montpellier 1&2 ("MIVEGEC"), Montpellier, France; Centre Hospitalier Régional Universitaire of Montpellier, Montpellier, France. Electronic address: genpara@univ-montp1.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bastien
mesh_terms: D002453:Cell Cycle / Q000235:genetics*; D049071:Endopeptidase Clp / Q000235:genetics* / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D018320:Leishmania major / Q000201:enzymology / Q000235:genetics*; D008018:Life Cycle Stages / Q000235:genetics; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics* / Q000378:metabolism; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014346:Trypanosoma brucei brucei / Q000201:enzymology / Q000235:genetics*
chemical_list: C483566:ClpYQ protease, E coli; D029968:Escherichia coli Proteins; D007527:Isoenzymes; D021122:Protein Subunits; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; D049071:Endopeptidase Clp; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
keywords: Drug target; HslVU; Leishmania; Proteasome; RNAinterference; Trypanosoma