Third target of rapamycin complex negatively regulates development of quiescence in Trypanosoma brucei.
African trypanosomes are protozoan parasites transmitted by a tsetse fly vector to a mammalian host. The life cycle includes highly proliferative forms and quiescent forms, the latter being adapted to host transmission. The signaling pathways controlling the developmental switch between the two forms remain unknown. Trypanosoma brucei contains two target of rapamycin (TOR) kinases, TbTOR1 and TbTOR2, and two TOR complexes, TbTORC1 and TbTORC2. Surprisingly, two additional TOR kinases are encoded in the T. brucei genome. We report that TbTOR4 associates with an Armadillo domain-containing protein (TbArmtor), a major vault protein, and LST8 to form a unique TOR complex, TbTORC4. Depletion of TbTOR4 caused irreversible differentiation of the parasite into the quiescent form. AMP and hydrolysable analogs of cAMP inhibited TbTOR4 expression and induced the stumpy quiescent form. Our results reveal unexpected complexity in TOR signaling and show that TbTORC4 negatively regulates differentiation of the proliferative form into the quiescent form.
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, 18100 Granada, Spain.
Antonio
A
Barquilla
Manuel
M
Saldivia
Rosario
R
Diaz
Jean-Mathieu
JM
Bart
Isabel
I
Vidal
Enrique
E
Calvo
Michael N
MN
Hall
Miguel
M
Navarro
D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000249:Adenosine Monophosphate / Q000494:pharmacology; D015153:Blotting, Western; D000242:Cyclic AMP / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014346:Trypanosoma brucei brucei / Q000502:physiology*; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism; D000099187:Major Vault Protein
D000249:Adenosine Monophosphate; D000242:Cyclic AMP; D046912:Multiprotein Complexes; D058570:TOR Serine-Threonine Kinases; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein