Mechanisms controlling metabolism by regulating protein turnover

Christiano R, Farese RJ and Walther TC

Harvard University/Howard Hughes Medical Institute..

Many metabolic reactions are tightly controlled. One mechanism for such control occurs through regulating the stability of key enzymes of metabolism. Such regulation is mediated by ubiquitin ligases, sorting factors, and proteases. To elucidate regulatory pathways, we globally investigated protein turnover a large sets of mutants in the degradative machinery in S. cerevisiae. Analysis of the resulting turnover map (T-MAP) revealed targets for most ubiquitin ligases and identified the primary degradation routes for most short-lived proteins. Illustrating the power of this approach, we uncovered new insights into ERAD pathways governing sterol synthesis and numerous previously unknown nodes of regulation for sphingolipid synthesis. Expansion of the T-MAP strategy in yeast and mammalian cells provides a powerful tool to unravel the contributions of protein degradation to proteostasis.