Intracellular parasitism with Toxoplasma gondii stimulates mammalian-target-of-rapamycin-dependent host cell growth despite impaired signalling to S6K1 and 4E-BP1.
The Ser/Thr kinase mammalian-target-of-rapamycin (mTOR) is a central regulator of anabolism, growth and proliferation. We investigated the effects of Toxoplasma gondii on host mTOR signalling. Toxoplasma invasion of multiple cell types rapidly induced sustained mTOR activation that was restricted to infected cells, as determined by rapamycin-sensitive phosphorylation of ribosomal protein S6; however, phosphorylation of the growth-associated mTOR substrates 4E-BP1 and S6K1 was not detected. Infected cells still phosphorylated S6K1 and 4E-BP1 in response to insulin, although the S6K1 response was blunted. Parasite-induced S6 phosphorylation was independent of S6K1 and did not require activation of canonical mTOR-inducing pathways mediated by phosphatidylinositol 3-kinase-Akt and ERK. Host mTOR was localized in a vesicular pattern surrounding the parasitophorous vacuole, suggesting potential activation by phosphatidic acid in the vacuolar membrane. In spite of a failure to phosphorylate 4E-BP1 and S6K1, intracellular T. gondii triggered host cell cycle progression in an mTOR-dependent manner and progression of infected cells displayed increased sensitivity to rapamycin. Moreover, normal cell growth was maintained during parasite-induced cell cycle progression, as indicated by total cellular S6 levels. The Toxoplasma-infected cell provides a unique example of non-canonical mTOR activation supporting growth that is independent of signalling through either S6K1 or 4E-BP1.
Wang
Yubao
Y
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Weiss
Louis M
LM
Orlofsky
Amos
A
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors*; D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D002468:Cell Physiological Phenomena; D003593:Cytoplasm / Q000737:chemistry; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011494:Protein Kinases / Q000096:biosynthesis*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014122:Toxoplasma / Q000472:pathogenicity*; D014617:Vacuoles / Q000469:parasitology
D048868:Adaptor Proteins, Signal Transducing; D006131:Growth Inhibitors; D038601:Ribosomal Protein S6; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus