TORC4 in a Parasite’s Life Cycle

Sci. Signal.  11 Sep 2012:
Vol. 5, Issue 241, pp. ec236
DOI: 10.1126/scisignal.2003592

Whereas most eukaryotes have only one or two genes encoding the kinase target of rapamycin (TOR), Trypanosoma and the related human pathogenic parasite Leishmania have four. TOR forms two functionally distinct complexes, TORC1 and TORC2. Barquilla et al. identified a third TOR complex, TbTORC4, containing the kinase TbTOR4, TbLST8 (a component common to all known TOR complexes), and TbArmtor (T. brucei Armadillo-containing TOR-interacting protein), a protein with an Armadillo domain that is unique to this TOR complex. During the Trypanosoma life cycle, the parasite is transferred from the mammalian host to the tsetse fly, which requires different forms of the parasite. In the mammalian host, bloodborne Trypanosoma differentiate from the slender proliferating form to a cell cycle–arrested “stumpy” form, which can survive and subsequently differentiate into a proliferative form in the insect. Trypanosomes isolated from the bloodstream of infected mice and in which TbTOR4 or TbArmtor was knocked down exhibited cell cycle arrest that was not readily reversed after recovery from knockdown, which is similar to the induction of the G0-arrested quiescent stumpy form. The trypanosomes in which TbTOR4 was depleted exhibited morphological, metabolic, and molecular characteristics of the stumpy form, suggesting that TbTORC4 inhibits the transition to this stage of the life cycle. Cells grown in the presence of either a hydrolyzable cyclic adenosine monophosphate (AMP) analog or an AMP analog exhibited a reduction in the abundance of TbTOR4, suggesting that reduced cellular energy (high AMP:ATP ratio) may inhibit TbTORC4 activity by reducing TbTOR4 abundance and thus promote the differentiation into the stumpy quiescent form. Because this complex appears unique to the parasite and is not present in the mammalian host, it may be a viable target for therapeutic intervention in the treatment of diseases arising from infection by parasites with TORC4.

A. Barquilla, M. Saldivia, R. Diaz, J.-M. Bart, I. Vidal, E. Calvo, M. N. Hall, M. Navarro, Third target of rapamycin complex negatively regulates development of quiescence in Trypanosoma brucei. Proc. Natl. Acad. Sci. U.S.A. 109, 14399–14404 (2012). [Abstract] [Full Text]