title: Mitochondrial peroxiredoxin functions as crucial chaperone reservoir in Leishmania infantum.
abstract: Cytosolic eukaryotic 2-Cys-peroxiredoxins have been widely reported to act as dual-function proteins, either detoxifying reactive oxygen species or acting as chaperones to prevent protein aggregation. Several stimuli, including peroxide-mediated sulfinic acid formation at the active site cysteine, have been proposed to trigger the chaperone activity. However, the mechanism underlying this activation and the extent to which the chaperone function is crucial under physiological conditions in vivo remained unknown. Here we demonstrate that in the vector-borne protozoan parasite Leishmania infantum, mitochondrial peroxiredoxin (Prx) exerts intrinsic ATP-independent chaperone activity, protecting a wide variety of different proteins against heat stress-mediated unfolding in vitro and in vivo. Activation of the chaperone function appears to be induced by temperature-mediated restructuring of the reduced decamers, promoting binding of unfolding client proteins in the center of Prx's ringlike structure. Client proteins are maintained in a folding-competent conformation until restoration of nonstress conditions, upon which they are released and transferred to ATP-dependent chaperones for refolding. Interference with client binding impairs parasite infectivity, providing compelling evidence for the in vivo importance of Prx's chaperone function. Our results suggest that reduced Prx provides a mitochondrial chaperone reservoir, which allows L. infantum to deal successfully with protein unfolding conditions during the transition from insect to the mammalian hosts and to generate viable parasites capable of perpetuating infection.
authors: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200 Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109;
authors: Filipa
authors: F
authors: Teixeira
authors: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200 Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal;
authors: Helena
authors: H
authors: Castro
authors: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200 Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal;
authors: Tânia
authors: T
authors: Cruz
authors: Life Science Institute, University of Michigan, Ann Arbor, MI 48109; and.
authors: Eric
authors: E
authors: Tse
authors: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109;
authors: Philipp
authors: P
authors: Koldewey
authors: Life Science Institute, University of Michigan, Ann Arbor, MI 48109; and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109.
authors: Daniel R
authors: DR
authors: Southworth
authors: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200 Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal; atomas@ibmc.up.pt ujakob@umich.edu.
authors: Ana M
authors: AM
authors: Tomás
authors: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109 atomas@ibmc.up.pt ujakob@umich.edu.
authors: Ursula
authors: U
authors: Jakob
mesh_terms: D000818:Animals; D018314:Leishmania infantum / Q000201:enzymology* / Q000472:pathogenicity; D008156:Luciferases / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D054464:Peroxiredoxins / Q000378:metabolism*; D017510:Protein Folding; D014774:Virulence
chemical_list: D018832:Molecular Chaperones; D054464:Peroxiredoxins; D008156:Luciferases
keywords: Leishmania; chaperone; peroxiredoxin
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