Sarov Prize - Basic Studies
A NETWORK OF CAP-BINDING PROTEINS IN THE SERVICE OF STRESS PHYSIOLOGY IN TRYPANOSOMATIDS

Protein synthesis must be tightly regulated during the life span of a cell, since exposure to extreme environmental conditions may lead to the formation of misfolded polypeptides that can further aggregate and become toxic. Under such circumstances global translation stops, allowing only exclusive proteins to continue to be synthesized, as they are required for survival under these unfavorable conditions. Global translation arrest can be achieved by inhibiting the canonical cap-dependent initiation, whereas the synthesis of specific proteins required for survival under stress conditions usually proceeds via alternative processes, possibly cap-independent. Trypanosomatids are digenetic parasites that migrate between invertebrate vectors and mammalian hosts, and therefore must adapt rapidly to extreme environments. Translation regulation plays a key role in their ability to control their changing proteomic profiles. We find that trypanosomatids encode for an unusual large repertoire of paralogs that are related to the translation initiation factors, and that these vary extensively in sequence, structure and function, as well as in the nature of interactions that hold the complexes together. To date, six paralogs of the cap-binding protein eIF4E have been identified, and a similar number of paralogs for the eIF4G scaffold protein, which in higher eukaryotes serves as a hub for the cap-anchored translation initiation complex. Our studies show that different cap-binding proteins are adapted to function in response to specific stress conditions that are part of the natural life cycle. These include abiotic stresses along with a temporary nutritional scarcity that they experience as well. Furthermore, we have identified unique and novel proteins that interact with specific cap-binding proteins in a substrate-specific manner, thus generating a complex network of cap-binding complexes. These regulators are not known from higher eukaryotes, and appear to assist in the remarkable adaptation of trypanosomatids to their changing conditions, as well as to the temporary lack of nutrients which they experience during their life cycle.