How cells adapt to Fe deficiency through targeted messenger RNA degradation

ITQB-Seminar

Title: How cells adapt to Fe deficiency through targeted messenger RNA degradation

Speaker: Dennis Thiele

Affiliation:- Full Professor "Duke University"

- Vice Chair, Department of Pharmacology and Cancer Biology, Duke University Medical Center"

Host: Claudina Rodrigues-Pousada Head of Genomics and Stress Laboratory

 Abstract:

How cells adapt to Fe deficiency through targeted messenger RNA degradation
Dennis Thiele, Duke University Medical Center
http://thielelab.duhs.duke.edu

Iron (Fe) serves as an essential metal ion cofactor for most life forms on this planet. Due to its ability to exist in an oxidized (Fe3+) or reduced (Fe2+) state, Fe drives catalytic reactions for enzymes involved in mitochondrial oxidative phosphorylation, oxygen transport, intermediary metabolism, chromatin remodelling and a host of other critical biochemical reactions. Fe deficiency leads to a number of severe health consequences in humans including anaemia and cognitive and developmental disorders. Indeed, Fe deficiency is the leading nutritional disorder on earth, thought to impact nearly 2 billion people, with disproportionate effects on pregnant women and children. Although Fe deficiency is so profound, we know very little about how cells dynamically alter their metabolism in response to changes in Fe availability. The baker yeast S. cerevisiae is an excellent organism for delineating the components involved in Fe acquisition, utilization and regulation. In response to Fe deficiency the Aft1/2 Fe-sensing transcription factors activate a Fe regulon comprising over 90 genes. Two Fe regulon genes, CTH1 and CTH2, encode RNA binding proteins that bind to AU-rich Elements (AREs) located in the 3’-UTR of mRNAs to induce the degradation of over 90 specific mRNAs. While the Cth1 and Cth2 proteins degrade mRNAs encoding Fe utilizing and storage proteins, thereby facilitating the cellular prioritization of limited Fe, they have only partially overlapping target mRNAs. Moreover, Cth1 and Cth2 appear to occupy distinct subcellular geography and are subject to additional regulatory controls that, together, regulate how yeast cells achieve rheostatic control during periods of Fe limitation and Fe supplementation. Understanding how Cth1 and Cth2 function, and the nature of their regulation and target genes, will provide a cellular wide view of the adaptive responses to a changing Fe landscape.