Intracellular iron homeostasis is a critical cellular process that ensures intracellular iron concentrations are sufficient to perform essential iron-dependent functions in aerobic respiration, DNA replication and repair, and multiple biosynthetic pathways (amino acid, nucleotide, and lipid) while avoiding the toxicity associated with excess iron. We previously identified the E3 ubiquitin ligase FBXL5 as a master regulator of iron homeostasis that was responsible for sensing intracellular iron levels through an N-terminal iron-binding domain and coupling changes in iron concentration to its ability to degrade Iron Regulatory Proteins (IRPs) - RNA binding proteins that the post-transcriptional expression of genes involved iron utilization, transport, and storage. In the proposed work, we will examine the hypothesis that FBLX5 is a key signaling hub that coordinates IRP- mediated gene regulation with variety of other iron metabolic pathways in order to generate an integrated cellular response to iron deficiency.
Specific aim 1 will explore the role of the Fe-S cluster assembly pathways in regulating iron homeostasis by characterizing a novel interaction identified in our laboratory between FBXL5 and the CIA targeting complex, a protein complex required for Fe-S protein biogenesis.
In specific aim 2, we will elucidate the cellular mechanism by which FBXL5 is degraded in iron-depleted cells by defining the roles of the E3 ubiquitin ligase HERC2 and the kinase SPAK in this proteolytic pathway. Finally, specific aim 3 will focus on examining a role for FBXL5 in regulating ferritin degradation via its association with the autophagy adaptor NCOA4. Investigation of these three aims will uncover the molecular mechanisms that govern how FBXL5 integrates and interprets signals transduced through multiple iron-regulated signaling pathways in order to dictate the multi-faceted cellular response to iron availability.

Public Health Relevance

The attachment of the small protein ubiquitin to specific targets in the cell is an important signal for cellular communication and used in a variety of physiological pathways. This proposal focuses on understanding how the ubiquitin system regulates different facets of iron metabolism. Considering defects in ion metabolism have been linked to many diseases including anemias, hemochromatosis, and cancer, elucidating how iron metabolism is regulated by ubiquitin will have important implications for understanding the molecular basis of these disorders.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Romero, Antonia M; Martínez-Pastor, Mar; Du, Gang et al. (2018) Phosphorylation and Proteasome Recognition of the mRNA-Binding Protein Cth2 Facilitates Yeast Adaptation to Iron Deficiency. MBio 9:
Harris, C Jake; Scheibe, Marion; Wongpalee, Somsakul Pop et al. (2018) A DNA methylation reader complex that enhances gene transcription. Science 362:1182-1186
Stehling, Oliver; Mascarenhas, Judita; Vashisht, Ajay A et al. (2018) Human CIA2A-FAM96A and CIA2B-FAM96B Integrate Iron Homeostasis and Maturation of Different Subsets of Cytosolic-Nuclear Iron-Sulfur Proteins. Cell Metab 27:263
Metz, Kyle A; Teng, Xinchen; Coppens, Isabelle et al. (2018) KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy-lysosome defect. Ann Neurol 84:766-780
Wu, Edlyn; Vashisht, Ajay A; Chapat, Clément et al. (2017) A continuum of mRNP complexes in embryonic microRNA-mediated silencing. Nucleic Acids Res 45:2081-2098
Steffen, Janos; Vashisht, Ajay A; Wan, Jijun et al. (2017) Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria. Mol Biol Cell 28:600-612
Fetherolf, Morgan M; Boyd, Stefanie D; Taylor, Alexander B et al. (2017) Copper-zinc superoxide dismutase is activated through a sulfenic acid intermediate at a copper ion entry site. J Biol Chem 292:12025-12040
Huang, Chengyang; Su, Trent; Xue, Yong et al. (2017) Cbx3 maintains lineage specificity during neural differentiation. Genes Dev 31:241-246
Li, Dongming; Palanca, Ana Marie S; Won, So Youn et al. (2017) The MBD7 complex promotes expression of methylated transgenes without significantly altering their methylation status. Elife 6:
Kerins, Michael John; Vashisht, Ajay Amar; Liang, Benjamin Xi-Tong et al. (2017) Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes. Mol Cell Biol 37:

Showing the most recent 10 out of 95 publications