The Wohlschlegel laboratory is broadly interested in how the ubiquitin pathway regulates the molecular processes that drive cell growth and proliferation and how this regulation is impaired in different pathological contexts. Currently, their research is focused in three major areas:

Iron Metabolism and the E3 Ligase FBXL5. In previous work, we identified FBXL5 as an E3 ubiquitin ligase that functions as a critical regulator of intracellular iron homeostasis. We found that FBXL5 catalyzes the ubiquitin-dependent degradation of Iron Regulatory Proteins 1 and 2 (IRP1/2), two RNA binding proteins that control the translation and/or stability of mRNAs that encode iron metabolic proteins involved in iron transport and storage. FBXL5 is also able to directly sense intracellular iron concentrations through an iron-binding hemerythrin-like domain present in its N-terminus. In iron replete conditions, iron-binding by FBXL5’s hemerythrin domain stabilizes the enzyme enabling it to degrade IRP1/2 while in iron-deficient conditions, FBXL5 is destabilized allowing IRP1/2 to accumulate and bind their target mRNAs. We are now continuing our characterization of FBXL5 by examining how FBXL5’s role as an iron sensor influences other pathways integral to iron metabolism such as Fe-S metabolism and ferritin degradation.