Iron is an essential nutrient that functions as a key co-factor for many cellular proteins involved in aerobic respiration, nucleotide metabolism, gene expression, and DNA repair. Given its central role in sustaining life, it is not surprising that cells have established a variety of elaborate regulatory mechanisms to control iron availability and usage. While characterizing components of the ubiquitination machinery that are deregulated in tumorigenesis, we identified a ubiquitin ligase subunit called FBXL5. In preliminary work, we demonstrated the FBXL5 is a novel regulator of iron metabolism that proteolytically controls the expression of important effectors of iron metabolism and cytoplasmic iron-sulfur cluster assembly. The major goal of this proposal is to examine the biological mechanisms by which FBXL5 regulates and is regulated by iron-related pathways.
In specific aim 1, we will examine the molecular basis of the iron-regulated interaction of FBXL5 with IRP2, a key regulator of iron homeostasis. The experiments in specific aim 2 will revolve around the regulation of FBXL5 itself and elucidating the novel proteolytic pathway responsible for its proteasome-dependent degradation under conditions of low iron availability.
Specific aim 3 will focus on the establishing the functional relevance of the interaction between FBXL5 and MMS19 and CIAO1, two putative components of the cytosolic iron assembly (CIA) pathway which is required for the assembly of Fe/S clusters in extramitochondrial proteins. Investigation of these three aims will provide a comprehensive view of how FBXL5 is able to influence multiple iron-associated processes. Ultimately, we hope that this work will offer insight into how the deregulation of FBXL5 and its downstream pathways may contribute to tumorigenesis while simultaneously highlighting potential new therapeutic strategies.

Public Health Relevance

The attachment of the ubiquitin to proteins is an important signal for cellular communication and is believed to be disrupted in multiple diseases including cancer, neurodegenerative diseases such as Huntington's disease, and diabetes. This proposal is focused on understanding how cells use this tagging system to regulate iron levels and usage.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM089778-04
Application #
8499363
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$285,647
Indirect Cost
$97,443
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
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
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
Wang, Qin; Barshop, William D; Bian, Mingdi et al. (2017) The Blue Light-Dependent Phosphorylation of the CCE Domain Determines the Photosensitivity of Arabidopsis CRY2. Mol Plant 10:357
Zhang, Ze; Ren, Ping; Vashisht, Ajay A et al. (2017) Cdk1-interacting protein Cip1 is regulated by the S phase checkpoint in response to genotoxic stress. Genes Cells 22:850-860
Chen, Allan L; Moon, Andy S; Bell, Hannah N et al. (2017) Novel insights into the composition and function of the Toxoplasma IMC sutures. Cell Microbiol 19:
Huang, Chengyang; Su, Trent; Xue, Yong et al. (2017) Cbx3 maintains lineage specificity during neural differentiation. Genes Dev 31:241-246
Liu, Qing; Wang, Qin; Deng, Weixian et al. (2017) Molecular basis for blue light-dependent phosphorylation of Arabidopsis cryptochrome 2. Nat Commun 8:15234
Nitarska, Justyna; Smith, Jacob G; Sherlock, William T et al. (2016) A Functional Switch of NuRD Chromatin Remodeling Complex Subunits Regulates Mouse Cortical Development. Cell Rep 17:1683-1698
Kumar, Vikas; Madina, Bhaskara R; Gulati, Shelly et al. (2016) REH2C Helicase and GRBC Subcomplexes May Base Pair through mRNA and Small Guide RNA in Kinetoplastid Editosomes. J Biol Chem 291:5753-64
Kwong, Pak N; Chambers, Michael; Vashisht, Ajay A et al. (2016) The central region of the Drosophila co-repressor Groucho as a regulatory hub. J Biol Chem 291:6784

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