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

Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14399-404. doi: 10.1073/pnas.1210465109. Epub 2012 Aug 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / drug effects
  • Adaptation, Physiological / physiology*
  • Adenosine Monophosphate / pharmacology
  • Blotting, Western
  • Cyclic AMP / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Immunoprecipitation
  • Microscopy, Fluorescence
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Signal Transduction / genetics*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Trypanosoma brucei brucei / physiology*
  • Vault Ribonucleoprotein Particles / metabolism

Substances

  • Multiprotein Complexes
  • Vault Ribonucleoprotein Particles
  • major vault protein
  • Adenosine Monophosphate
  • Cyclic AMP
  • TOR Serine-Threonine Kinases