Molecular control of irreversible bistability during trypanosome developmental commitment

Maria Rosa Domingo-Sananes, Balazs Szöor, Michael A J Ferguson, Michael D. Urbaniak (Lead / Corresponding author), Keith R. Matthews (Lead / Corresponding author)

Research output: Contribution to journalArticle

24 Citations (Scopus)
175 Downloads (Pure)

Abstract

The life cycle of Trypanosoma brucei involves developmental transitions that allow survival, proliferation, and transmission of these parasites. One of these, the differentiation of growth-arrested stumpy forms in the mammalian blood into insect-stage procyclic forms, can be induced synchronously in vitro with cis-aconitate. Here, we show that this transition is an irreversible bistable switch, and we map the point of commitment to differentiation after exposure to cis-aconitate. This irreversibility implies that positive feedback mechanisms operate to allow commitment (i.e., the establishment of "memory" of exposure to the differentiation signal). Using the reversible translational inhibitor cycloheximide, we show that this signal memory requires new protein synthesis. We further performed stable isotope labeling by amino acids in cell culture to analyze synchronized parasite populations, establishing the protein and phosphorylation profile of parasites pre- and postcommitment, thereby defining the "commitment proteome." Functional interrogation of this data set identified Nek-related kinase as the first-discovered protein kinase controlling the initiation of differentiation to procyclic forms.

Original languageEnglish
Pages (from-to)455-468
Number of pages14
JournalJournal of Cell Biology
Volume211
Issue number2
DOIs
Publication statusPublished - 19 Oct 2015

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