Protein phosphatase 5 is required for Hsp90 function during proteotoxic stresses in Trypanosoma brucei.
Trypanosoma brucei, a parasitic protozoan that causes African trypanosomiasis in human and domestic animals, adapt in various environments during their digenetic life cycle. In this study, we found that Hsp90 is crucial for the survival of this parasite. Inhibition of Hsp90 activity by geldanamycin (GA) reduced cell growth and increased the level of Hsp90. Both the bloodstream and procyclic forms of T. brucei showed a several-fold greater sensitivity than the mammalian cells to GA and also to 17-AAG, a less toxic derivative of GA, suggesting that Hsp90 could be a potential chemotherapeuric target for African trypanosomiasis. T. brucei Hsp90 interacts with the protein phosphatase 5 (PP5) in vivo. Under normal growth conditions, T. brucei PP5 (TbPP5) and Hsp90 are primarily localized in the cytosol. However, with increase in growth temperature and GA treatment, these proteins translocate to the nucleus. Overproduction of TbPP5 by genetic manipulation reduced the growth inhibitory effect of GA, while knockdown of TbPP5 reduced cell growth more in the presence of GA, as compared to parental control. Depletion of TbPP5, however, did not prevent the induction of Hsp90 protein level during GA treatment. Together, these results suggest that TbPP5 positively regulates the function of Hsp90 to maintain cellular homeostasis during proteotoxic stresses in T. brucei.
Jones
Candace
C
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
Anderson
Sedrick
S
Singha
Ujjal K
UK
Chaudhuri
Minu
M
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008018:Life Cycle Stages; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development / Q000502:physiology*
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009687:Nuclear Proteins; D015800:Protozoan Proteins; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5; C001277:geldanamycin