Identification of longevity targets in C. elegans protein translation mutants

Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): The research proposed in this fellowship application addresses an extremely interesting question in the field of aging and mRNA translation: How come many organisms, including the nematode C. elegans defective in key components of the mRNA translational machinery are long-lived and stress resistant? Interestingly, in response to environmental stress, all eukaryotic cells shut down their biosynthetic activity and mount an integrated stress response. During recovery, certain proteins are produced against the backdrop of general translational repression. The main objective of the present application is to uncover the biochemical mechanisms that enable the escape of stress-induced mRNAs from translational repression during the stress response and the actively translated mRNAs involved in the longevity phenotype. The project will examine the hypothesis that key translational regulatory factors belonging to either S6 kinase (S6K) and/or the group of eukaryotic translation initiation factors (eIFs) can specifically mediate this escape. The focus will be on rsks-1/ S6K, as well as on ife-2/eIF4E, one of five isoforms in worms that is an mRNA 5'-cap binding protein. Both S6K and eIF4E may be at the heart of regulating a pathway that mediates stress-specific and longevity translation. The main question to be addressed is: What are S6K and eIF4E downstream translational targets that need to be synthesized in order to allow survival under stress and aging? This question will be addressed with a series of cutting-edge ribonomic and proteomic approaches using the nematode, C. elegans as an experimental system. The model organism is extremely useful for aging research because of its rapid development, short lifespan, and the ability to knock-out genes through RNAi with great ease.