TY - JOUR
T1 - TrypOx, a Novel Eukaryotic Homolog of the Redox-Regulated Chaperone Hsp33 in Trypanosoma brucei
AU - Aramin, Samar
AU - Fassler, Rosi
AU - Chikne, Vaibhav
AU - Goldenberg, Mor
AU - Arian, Tal
AU - Kolet Eliaz, Liat
AU - Rimon, Oded
AU - Ram, Oren
AU - Michaeli, Shulamit
AU - Reichmann, Dana
N1 - Publisher Copyright:
© Copyright © 2020 Aramin, Fassler, Chikne, Goldenberg, Arian, Kolet Eliaz, Rimon, Ram, Michaeli and Reichmann.
PY - 2020/8/6
Y1 - 2020/8/6
N2 - ATP-independent chaperones are widespread across all domains of life and serve as the first line of defense during protein unfolding stresses. One of the known crucial chaperones for bacterial survival in a hostile environment (e.g., heat and oxidative stress) is the highly conserved, redox-regulated ATP-independent bacterial chaperone Hsp33. Using a bioinformatic analysis, we describe novel eukaryotic homologs of Hsp33 identified in eukaryotic pathogens belonging to the kinetoplastids, a family responsible for lethal human diseases such as Chagas disease as caused by Trypanosoma cruzi, African sleeping sickness caused by Trypanosoma brucei spp., and leishmaniasis pathologies delivered by various Leishmania species. During their pathogenic life cycle, kinetoplastids need to cope with elevated temperatures and oxidative stress, the same conditions which convert Hsp33 into a powerful chaperone in bacteria, thus preventing aggregation of a wide range of misfolded proteins. Here, we focused on a functional characterization of the Hsp33 homolog in one of the members of the kinetoplastid family, T. brucei, (Tb927.6.2630), which we have named TrypOx. RNAi silencing of TrypOx led to a significant decrease in the survival of T. brucei under mild oxidative stress conditions, implying a protective role of TrypOx during the Trypanosomes growth. We then adopted a proteomics-driven approach to investigate the role of TrypOx in defining the oxidative stress response. Depletion of TrypOx significantly altered the abundance of proteins mediating redox homeostasis, linking TrypOx with the antioxidant system. Using biochemical approaches, we identified the redox-switch domain of TrypOx, showing its modularity and oxidation-dependent structural plasticity. Kinetoplastid parasites such as T. brucei need to cope with high levels of oxidants produced by the innate immune system, such that parasite-specific antioxidant proteins like TrypOx – which are depleted in mammals – are highly promising candidates for drug targeting.
AB - ATP-independent chaperones are widespread across all domains of life and serve as the first line of defense during protein unfolding stresses. One of the known crucial chaperones for bacterial survival in a hostile environment (e.g., heat and oxidative stress) is the highly conserved, redox-regulated ATP-independent bacterial chaperone Hsp33. Using a bioinformatic analysis, we describe novel eukaryotic homologs of Hsp33 identified in eukaryotic pathogens belonging to the kinetoplastids, a family responsible for lethal human diseases such as Chagas disease as caused by Trypanosoma cruzi, African sleeping sickness caused by Trypanosoma brucei spp., and leishmaniasis pathologies delivered by various Leishmania species. During their pathogenic life cycle, kinetoplastids need to cope with elevated temperatures and oxidative stress, the same conditions which convert Hsp33 into a powerful chaperone in bacteria, thus preventing aggregation of a wide range of misfolded proteins. Here, we focused on a functional characterization of the Hsp33 homolog in one of the members of the kinetoplastid family, T. brucei, (Tb927.6.2630), which we have named TrypOx. RNAi silencing of TrypOx led to a significant decrease in the survival of T. brucei under mild oxidative stress conditions, implying a protective role of TrypOx during the Trypanosomes growth. We then adopted a proteomics-driven approach to investigate the role of TrypOx in defining the oxidative stress response. Depletion of TrypOx significantly altered the abundance of proteins mediating redox homeostasis, linking TrypOx with the antioxidant system. Using biochemical approaches, we identified the redox-switch domain of TrypOx, showing its modularity and oxidation-dependent structural plasticity. Kinetoplastid parasites such as T. brucei need to cope with high levels of oxidants produced by the innate immune system, such that parasite-specific antioxidant proteins like TrypOx – which are depleted in mammals – are highly promising candidates for drug targeting.
KW - Hsp33
KW - holdase chaperone
KW - redox regulation
KW - redox regulation in T. brucei
KW - stress-regulated chaperones
UR - http://www.scopus.com/inward/record.url?scp=85089806472&partnerID=8YFLogxK
U2 - 10.3389/fmicb.2020.01844
DO - 10.3389/fmicb.2020.01844
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 32849441
AN - SCOPUS:85089806472
SN - 1664-302X
VL - 11
JO - Frontiers in Microbiology
JF - Frontiers in Microbiology
M1 - 1844
ER -