Dynamic localization of the chromosomal passenger complex in trypanosomes is controlled by the orphan kinesins KIN-A and KIN-B

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Authors

Ballmer, D., and Akiyoshi, B.

Summary of Paper by Melanie Lim, Marston Lab

During mitotic chromosome segregation, sister kinetochores must attach to microtubules from opposite poles. Faulty attachments must be corrected, achieved in part by the multi-component chromosomal passenger complex (CPC). During prometaphase the CPC catalytic module, Aurora B kinase-INCENP, is targeted to kinetochores and destabilises erroneous kinetochore-microtubule attachments. As cells transition to anaphase, the CPC becomes spindle-associated in preparation for cytokinesis. The dynamic whereabouts of CPC depend on its localisation module proteins (Borealin, Survivin in humans).

The Akiyoshi lab noticed that Aurora B^AUK1-INCENP^CPC1 are conserved in the sleeping sickness-causing parasite Trypanosoma brucei, yet Borealin and Survivin homologues are absent. Their paper, published in eLife, reports how Aurora B^AUK1 is dynamically targeted in this evolutionarily divergent eukaryote.

Firstly, the authors confirmed that two orphan kinesins, KIN-A and KIN-B, interact with Aurora B^AUK1 and have an Aurora B^AUK1-like localisation pattern throughout the cell cycle. Kinesins are ATP-hydrolysing proteins that track along microtubules. Crucially, KIN-A or KIN-B depletion by RNAi led to the loss of Aurora B^AUK1-INCENP^CPC1 from kinetochores, identifying KIN-A and KIN-B as components of the T. brucei CPC localisation module.

Following on from this, the authors identified kinetochore proteins KKT7 and KKT9 as receptors demarcating chromosomal binding sites for KIN-A and KIN-B through extensive biochemistry, AlphaFold2 modelling and crosslinking mass spectrometry. Further experiments attributed the ATPase activity and two C-terminal conserved domains as crucial for kinetochore- and central spindle-targeting of CPC by KIN-A. While these findings uncover mechanistic details for T. brucei CPC recruitment, KIN-A and KIN-B are also present in other disease-causing kinetoplastids such as T. cruzi and Leishmania. If these parasites also utilise a KIN-A/ B-dependent mechanism for CPC localisation, then these kinesins are potential drug targets to combat kinetoplastid diseases and reduce their burden on the health of humans and livestock.

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