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PNAS 109 (36): 14399-14404

Copyright © 2012 by the National Academy of Sciences.


Third target of rapamycin complex negatively regulates development of quiescence in Trypanosoma brucei

Antonio Barquillaa, Manuel Saldiviaa, Rosario Diaza, Jean-Mathieu Barta,b, Isabel Vidala, Enrique Calvoc, Michael N. Halld, and Miguel Navarroa,1

aInstituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (CSIC), 18100 Granada, Spain; bCentro Nacional de Medicina Tropical, The Institute of Health Carlos III, 28029 Madrid, Spain; c Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain; and dBiozentrum, University of Basel, CH4056 Basel, Switzerland

Edited by Alberto Carlos Frasch, Universidad de San Martin and National Research Council, San Martin, Argentina, and approved July 27, 2012 (received for review June 21, 2012)

Abstract: 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.

Key Words: parasitology • cell biology • kinetoplastida

Author contributions: A.B., M.N.H., and M.N. designed research; A.B., M.S., R.D., and J.-M.B. performed research; A.B., M.S., I.V., and E.C. contributed new reagents/analytic tools; A.B., M.S., R.D., J.-M.B., and M.N. analyzed data; and A.B., M.N.H., and M.N. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: miguel.navarro{at}

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