FRET-detectable interactions between the ARE binding proteins, HuR and p37AUF1
Open accessAbstract
A number of highly regulated gene classes are regulated post-transcriptionally at the level of mRNA stability. A central feature in these mRNAs is the presence of A+U-rich elements (ARE) within their 3′ UTRs. Two ARE binding proteins, HuR and AUF1, are associated with mRNA stabilization and destabilization, respectively. Previous studies have demonstrated homomultimerization of each protein and the capacity to bind simultaneous or competitively to a single ARE. To investigate this possibility further, cell biological and biophysical approaches were undertaken. Protein–protein interaction was monitored by fluorescence resonance energy transfer (FRET) and by immunocytochemistry in live and fixed cells using fluorescently labeled CFP/YFP fusion proteins of HuR and p37AUF1. Strong nuclear FRET between HuR/HuR and AUF1/AUF1 homodimers as well as HuR/AUF1 heterodimers was observed. Treatment with the MAP kinase activator, anisomycin, which commonly stabilizes ARE-containing mRNAs, caused rapid nuclear to cytoplasmic shuttling of HuR. AUF1 also underwent shuttling, but on a longer time scale. After shuttling, HuR/HuR, AUF1/AUF1, and HuR/AUF1, FRET was also observed in the cytoplasm. In further studies, arsenite rapidly induced the formation of stress granules containing HuR and TIA-1 but not AUF1. The current studies demonstrate that two mRNA binding proteins, HuR and AUF1, are colocalized and are capable of functional interaction in both the nucleus and cytoplasm. FRET-based detection of AUF1/HuR interaction may serve as a basis of opening up new dimensions in delineating the functional interaction of mRNA binding proteins with RNA turnover.
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These interactions require the presence of RNA, since HuR and AUF1 were shown to simultaneously or competitively bind onto exclusive or common cis-acting elements in the 3′ UTRs of p21cip1/waf1, Cyclin D, TNFα, and β2-adrenergic receptor mRNAs.
“Moreover, these interactions require the presence of RNA, since HuR and AUF1 were shown to simultaneously or competitively bind onto exclusive or common, respectively, cis-acting elements in the 3′ UTRs of p21cip1/waf1, Cyclin D, TNFα, and β2-adrenergic receptor mRNAs (Lal et al. 2004; David et al. 2007).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as David et al. 2007
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Experimental — accuracy not yet measuredHuR interacts with AUF1, KSRP, and TIA-1 in the nucleus and cytoplasmic stress granules.
“Fluorescence resonance energy transfer (FRET) and biochemical techniques revealed that HuR interacts with AUF1, KSRP, and TIA-1 in the nucleus and cytoplasmic stress granules (David et al. 2007; David Gerecht et al. 2010).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as David et al. 2007
The section on FRET-detected complexes reports a HuR–p37AUF1 interaction in the nucleus. But the stress-granule section says HuR colocalizes with TIA-1 while AUF1 does not enter the granules; colocalization does not establish an interaction with TIA-1. The paper mentions KSRP but does not report a HuR–KSRP interaction. Page numbers are unavailable in our copy. (LLM, conf=0.90)
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- Fan, X.C. and Steitz, J.A. 1998a. HNS, a nuclear-cytoplasmic shuttling sequence in HuR. Proc. Natl. Acad. Sci. 95: 15293-15298.
- Kedersha, N. and Anderson, P. 2002. Stress granules: Sites of mRNA triage that regulate mRNA stability and translatability. Biochem. Soc. Trans. 30: 963-969.
- Mazan-Mamczarz, K., Galban, S., Lopez de Silanes, I., Martindale, J.L., Atasoy, U., Keene, J.D., and Gorospe, M. 2003. RNA-binding protein HuR enhances p53 translation in response to ultraviolet light irradiation. Proc. Natl. Acad. Sci. 100: 8354- 8359.
- Newbury, S.F., Muhlemann, O., and Stoecklin, G. 2006. Turnover in the Alps: An mRNA perspective. Workshops on mechanisms and regulation of mRNA turnover. EMBO Rep. 7: 143-148.
- FRET-detectable HuR/AUF1 interactions www.rnajournal.org 1467 Cold Spring Harbor Laboratory Press on July 19, 2023 -Published by rnajournal.cshlp.org Downloaded from
- Vogel, S.S., Thaler, C., and Koushik, S.V. 2006. Fanciful FRET. Sci. STKE 2006: re2. doi: 10.1126/stke.3312006re2. · DOI
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Diverse molecular functions of Hu proteins
Hinman, M. N., & Lou, H. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8252-6 · Cited by 587 · see citing works
Ljubicic, V., Joseph, A.-M., Saleem, A., Uguccioni, G., Collu-Marchese, M., Lai, R. Y. J., Nguyen, L. M.-D., & Hood, D. A. (2010) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2009.07.031 · Cited by 167 · see citing works
Bronicki, L. M., & Jasmin, B. J. (2013) · RNA · doi:10.1261/rna.039164.113 · Cited by 126 · see citing works
Intracellular localization and interaction of mRNA binding proteins as detected by FRET
David Gerecht, P. S., Taylor, M. A., & Port, J. D. (2010) · BMC Cell Biology · doi:10.1186/1471-2121-11-69 · Cited by 22 · see citing works
Self-citation
- Authors
- David, P. S., Tanveer, R., & Port, J. D.
- Affiliations
- University of Colorado Health (US)
- ORCID
- Port, J. David
- Venue
- RNA
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-07-12
- Volume
- 13
- Issue
- 9
- Pages
- 1453-1468
- ISSN
- 1355-8382 (ISSN-L)
- 1469-9001
- PMC
- PMC1950754
- OpenAlex
- W2062574977
- Cited by
- 72
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 3 · 2014: 7 · 2013: 6 · 2012: 8
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- RNA (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL051239)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- HuR, AUF1, AU-rich elements, mRNA stability, post-transcriptional regulation, protein-protein interaction, homodimerization, heterodimerization, nucleocytoplasmic shuttling, stress granules, TIA-1, arsenite, anisomycin, mitogen-activated protein kinase, 3' untranslated region, mRNA-binding proteins
- MeSH terms
- ELAV-Like Protein 1, Heterogeneous Nuclear Ribonucleoprotein D0, Animals, Antigens, Surface, Cell Line, Cell Nucleus, Cytoplasm, Cricetinae, Humans, Protein Binding, RNA, Messenger, RNA-Binding Proteins, Protein Interaction Mapping, Fluorescence Resonance Energy Transfer, Heterogeneous-Nuclear Ribonucleoprotein D, ELAV Proteins
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