An Alba-domain protein required for proteome remodelling during trypanosome differentiation and host transition

The transition between hosts is a challenge for digenetic parasites as it is unpredictable. For Trypanosoma brucei subspecies, which are disseminated by tsetse flies, adaptation to the new host requires differentiation of stumpy forms picked up from mammals to procyclic forms in the fly midgut. Here we show that the Alba-domain protein Alba3 is not essential for mammalian slender forms, nor is it required for differentiation of slender to stumpy forms in culture or in mice. It is crucial, however, for the development of T. brucei procyclic forms during the host transition. While steady state levels of mRNAs in differentiating cells are barely affected by the loss of Alba3, there are major repercussions for the proteome. Mechanistically, Alba3 aids differentiation by rapidly releasing stumpy forms from translational repression and stimulating polysome formation. In its absence, parasites fail to remodel their proteome appropriately, lack components of the mitochondrial respiratory chain and show reduced infection of tsetse. Interestingly, Alba3 and the closely related Alba4 are functionally redundant in slender forms, but Alba4 cannot compensate for the lack of Alba3 during differentiation from the stumpy to the procyclic form. We postulate that Alba-domain proteins play similar roles in regulating translation in other protozoan parasites, in particular during life-cycle and host transitions. Author summary Trypanosoma brucei is a unicellular eukaryotic parasite that is responsible for African trypanosomiasis. The parasite needs two hosts, mammals and tsetse flies, in order to complete its life cycle. Throughout its developmental cycle, T. brucei encounters diverse environments to which it has to adapt in order to maintain its transmission and infectivity. Successful adaptation to the new environment and transition to different life-cycle stages are the general challenges faced by many digenetic parasites. In this study we show that the Alba-domain protein Alba3 is essential for differentiation of the mammalian stumpy form (transition form) to the procyclic form in the tsetse host. An Alba3 deletion mutant infects mice and shows characteristic waves of parasitaemia, but is severely compromised in its ability to infect tsetse flies. Stumpy forms are translationally repressed, but are poised to resume protein synthesis during differentiation. We show that Alba3 is key to efficient escape from translation repression; in its absence, there is a delay in the formation of polysomes and resumption of protein synthesis. This impacts the formation of procyclic-specific mitochondrial respiratory complex proteins as well as the repression of some bloodstream-specific proteins. This is the first time that a single protein has been shown to have a major influence on translation as an adaptive response to changing hosts. It is also the first time that a mechanism has been established for Alba-domain proteins in parasites.

Automated summary

The Alba3 protein is crucial for Trypanosoma brucei in transitioning from the mammalian stumpy form to the procyclic form in tsetse flies. Its absence leads to deficiencies in protein synthesis, especially in mitochondrial respiratory proteins, affecting parasite infectivity. This study highlights the importance of Alba-domain proteins in translation regulation during host transitions for protozoan parasites.