Systematic Identification of TOR Downstream Effectors Using
Random-Walks on the Yeast Interactome
Shahin Mohammadi, Shankar Subramaniam, and Ananth Grama
Calorie restriction (CR), without malnutrition, is one of the most conserved non-genetic interventions that extends both the mean, and the maximum life-span in evolutionarily distant species, ranging from yeast to mammals. The target of rapamycin (TOR) has been shown to play a key role in mediating life-span extension in response to the CR, by modulating cellular response to nutrient-availability and orchestrating various components of cellular machinery, including cell growth, translation initiation, ribosome biogenesis, and autophagy. Furthermore, both genetic and pharmacological interventions inhibiting the TOR pathway exhibit a similar phenotype, which can not be further extended by CR. These observations have motivated experimental investigations of downstream effectors of TOR, which are responsible for mediating life-span extension.
In this paper, we derive the first comprehensive computational map of downstream effectors of TOR. We adopt a systematic approach, based on the known random-walk method for tracing information flow in the yeast interactome. Using a rigorous statistical framework, we identify targets carrying significant amounts of TOR signaling. Our approach, unlike experimental methods, is not limited to specific aspects of cellular response. Rather, it is shown to predict transcriptional changes, as well as post-translational modifications in response to TOR signaling. GO enrichment analysis of the identified effectors not only sheds light on the functional mechanisms downstream of TOR, but also provides mechanistic understanding of the crosstalk among them. In addition to identifying several known effectors, our method also identifies a number of other targets, whose roles have been hypothesized in literature but not confirmed; as well as potential new targets.
Keywords: Computational Aging, Information Flow Analysis, Yeast