Discussion

The bloodstream African trypanosome surface is protected from immune attack by a super-abundant variant surface glycoprotein (VSG) coat that is required for cytokinesis. These protozoa also display other unusual cell-cycle controls and readily uncouple S-phase and cytokinesis, producing multinucleated ‘monster’ cells when cellular architecture is disrupted. We find that VSG mRNA promotes S-phase and, in the absence of (VSG)-protein, the production of multinucleated cells. We used MS2 coat protein (MS2-cp) to block translation of a transgenic VSG mRNA containing a cognate hairpin in the 5´-untranslated-region; VSG mRNA abundance increased under these conditions. Like VSG mRNA knockdown, a VSG translation block triggered global translation arrest and cytokinesis arrest. In contrast to VSG mRNA knockdown, however, S-phase and mitosis continued in the presence of blocked VSG mRNA. Indeed, these cells re-entered S-phase and mitosis, yielding multi-nucleated trypanosomes. S-phase and cytokinesis uncoupling, triggered by defects in VSG-translation or trafficking, may explain why perturbations of cellular architecture often produce multi-nucleated cells. Our results reveal a bloodstream stage-specific VSG expression sensing mechanism that controls key cell-cycle phases, with the mRNA and protein coat promoting DNA replication and cytokinesis, respectively.