Eukaryotic cells have established a robust system for regulating intracellular iron homeostasis based on the E3 ubiquitin ligase FBXL5 and its degradation of Iron Regulatory Proteins 1 and 2 (IRPs). In earlier funding periods, we established a paradigm in which FBXL5 acts as a signaling hub that integrates different physiological signals to coordinate the downstream IRP-mediated gene expression program. This application builds on that foundation to examine how signaling through the Fe-S cluster assembly, oxygen metabolism, and cell cycle pathways regulates the FBXL5-IRP axis.
Specific aim 1 focuses on defining the mechanism by which the O2-dependent interaction of FBXL5 with the CIA targeting complex regulates IRP degradation.
In specific aim 2, we test the hypothesis that degradation of the E3 ubiquitin ligase pVHL by FBXL5 regulates the response of cells to hypoxia. The experiments in specific aim 3 will examine the interplay between FBXL5 and cell cycle progression pathways to coordinate cell proliferation with metabolism. Together, these three aims will uncover the molecular mechanisms that govern how FBXL5 integrates and interprets signals transduced through multiple signaling pathways in order to dictate the multi-faceted cellular response to iron availability.

Public Health Relevance

Defects in iron metabolism have been linked to many diseases including anemia, hemochromatosis, and cancer. This proposal focuses on characterizing FBXL5, a key component of this pathway, and how it is regulated by other cellular signals including cell cycle and oxygen. Understanding how these different environmental cues influences FBXL5 function has important implications for elucidating the molecular basis of these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM089778-10
Application #
9995778
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Maas, Stefan
Project Start
2010-07-01
Project End
2024-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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:

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