Mitochondrial peroxiredoxin functions as crucial chaperone reservoir inLeishmania 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.chaperone | Leishmania | peroxiredoxin

Peroxiredoxins: guardians against oxidative stress and modulators of peroxide signaling

“…In many eukaryotes, including humans, the enzyme Srx catalyzes repair of hyperoxidized Prxs in the Prx1 group (see next section), restoring their activity [17, 30]. Given that Prxs are abundant and highly reactive with cellular peroxides and peroxynitrite, and have activity that can be regulated, they are well suited to play roles not just in oxidant defense, but also in redox sensing and signaling and perhaps even in the recovery of oxidatively-damaged proteins [31–36]. The various physiological roles of Prxs can be better understood in the context of structural and functional features that are shared between certain members.…”

Stress-Activated Chaperones: A First Line of Defense

“…In addition, however, certain members of the Prx family reversibly lose their peroxidase function and switch into effective ATP-independent chaperones (Figure 3). Stress conditions that trigger chaperone activation of Prxs include severe peroxide stress (e.g., yeast Tsa1, mammalian hPrxII), which is mediated by the overoxidation of the active site cysteine [84, 85], low pH (e.g., SmPrxI from the trematode Schistosoma mansoni ) [86], or elevated temperatures (e.g ., mitochondrial mTXNPx from Leishmania infantum , C2C-Prx1 from Chinese cabbage) (Figure 3) [87, 88]. Because we discussed the mechanisms used to sense elevated ROS levels and acidic pH in some detail, we will focus this final discussion on the temperature sensing mechanism of mitochondrial mTXNPx from the parasite L. infantum .…”

Protein Quality Control under Oxidative Stress Conditions

“…One group of proteins that might be involved in this process are 2-Cys peroxiredoxins, which have been shown to gain chaperone activity upon peroxide-mediated overoxidation of their active site cysteine (for a more detailed overview see (109–111)). Recent studies however suggest that overoxidation is not essential and that other triggers, including high temperature and low pH (112, 113) might activate the chaperone function of peroxiredoxin as well. This makes peroxiredoxin less of a specialized and more of a general ATP-independent chaperone, which protects cells against a variety of different stress conditions, including oxidative stress.…”