Trypanosoma cruzi targets Akt in host cells as an intracellular antiapoptotic strategy.
The parasite Trypanosoma cruzi, which causes Chagas' disease, differentiates in the cytosol of its host cell and then replicates and spreads infection, processes that require the long-term survival of the infected cells. Here, we show that in the cytosol, parasite-derived neurotrophic factor (PDNF), a trans-sialidase that is located on the surface of T. cruzi, is both a substrate and an activator of the serine-threonine kinase Akt, an antiapoptotic molecule. PDNF increases the expression of the gene that encodes Akt while suppressing the transcription of genes that encode proapoptotic factors. Consequently, PDNF elicits a sustained functional response that protects host cells from apoptosis induced by oxidative stress and the proinflammatory cytokines tumor necrosis factor-alpha and transforming growth factor-beta. Given that PDNF also activates Akt by binding to the neurotrophic surface receptor TrkA, we propose that this protein activates survival signaling both at the cell surface, by acting as a receptor-binding ligand, and inside cells, by acting as a scaffolding adaptor protein downstream of the receptor.
Chuenkova
Marina V
MV
Parasitology Research Center, Department of Pathology, Tufts University School of Medicine, 150 Harrison Avenue, Boston, MA 02111, USA.
PereiraPerrin
Mercio
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006790:Host-Parasite Interactions; D006801:Humans; D047468:Immunoprecipitation; D042541:Intracellular Space / Q000378:metabolism / Q000469:parasitology; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism / Q000469:parasitology; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000201:enzymology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D006023:Glycoproteins; D015800:Protozoan Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; C069715:trans-sialidase; D009439:Neuraminidase