RNA-Binding Protein HuD Controls Insulin Translation
Open accessAbstract
Although expression of the mammalian RNA-binding protein HuD was considered to be restricted to neurons, we report that HuD is present in pancreatic β cells, where its levels are controlled by the insulin receptor pathway. We found that HuD associated with a 22-nucleotide segment of the 5' untranslated region (UTR) of preproinsulin (Ins2) mRNA. Modulating HuD abundance did not alter Ins2 mRNA levels, but HuD overexpression decreased Ins2 mRNA translation and insulin production, and conversely, HuD silencing enhanced Ins2 mRNA translation and insulin production. Following treatment with glucose, HuD rapidly dissociated from Ins2 mRNA and enabled insulin biosynthesis. Importantly, HuD-knockout mice displayed higher insulin levels in pancreatic islets, while HuD-overexpressing mice exhibited lower insulin levels in islets and in plasma. In sum, our results identify HuD as a pivotal regulator of insulin translation in pancreatic β cells.
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Quantitative RT-PCR and Western blot analysis revealed relatively minor, although significant, HuD mRNA and protein levels in several nonneuronal tissues including lung, testes, liver, pituitary gland, pancreatic β cells, and fiber cells of the lens.
“In addition to being expressed in various neuronal subpopulations in the CNS and PNS, quantitative RT-PCR and Western blot analysis revealed relatively minor, although significant, HuD mRNA and protein levels in several nonneuronal tissues including lung, testes, liver, pituitary gland, pancreatic β cells, and fiber cells of the lens (Abdelmohsen et al. 2010; Bitel et al. 2010; Lee et al. 2012).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Lee et al. 2012
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Experimental — accuracy not yet measuredPrior to our study, only two transcriptional mechanisms were known to regulate expression of the HuD gene: thyroid hormone (T3) and FoxO1, and both negatively impact the abundance of HuD.
“Prior to our study, only two transcriptional mechanisms were known to regulate expression of the HuD gene—thyroid hormone (T3; presumably via activation of the thyroid hormone receptor) and TF forkhead box O1 (FoxO1)—and both of these factors were shown to negatively impact the abundance of HuD.”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Lee et al. 2012
The Results section (‘HuD is expressed in pancreatic β cells’; page not provided) shows that FoxO1 binds the HuD promoter and that FoxO1 overexpression reduces HuD, supporting its role as a negative transcriptional regulator. The passages found do not address thyroid hormone (T3) or establish that these were the only two known transcriptional mechanisms. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTranslational silencing by HuD requires binding to an internal ribosome entry site (IRES) in the 5′ UTR of p27 mRNA and a short approximately 22-nt sequence in the 5′ UTR of Ins2 mRNA.
“Even though the mechanism of translational silencing is unclear, it was demonstrated to require HuD binding to an internal ribosome entry site (IRES) in the 5′ UTR of p27 mRNA (Kullmann et al. 2002) and a short ∼22-nt sequence in the 5′ UTR of Ins2 mRNA (Lee et al. 2012).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Lee et al. 2012
Repression of Ins2 translation by HuD is likely required to maintain insulin homeostasis.
“On the other hand, the study by Lee et al. showed that the repression of Ins2 translation by HuD is likely required to maintain insulin homeostasis (Lee et al. 2012).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Lee et al. 2012
HuD is capable of repressing protein synthesis, as shown for p27 and preproinsulin (Ins2) mRNAs.
“In addition to enhancing translation, HuD is capable of repressing protein synthesis, as shown for p27 and preproinsulin (Ins2) mRNAs (Kullmann et al. 2002; Lee et al. 2012).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Lee et al. 2012
FoxO1 negatively regulates transcription of HuD under low glucose conditions in pancreatic β cells.
“whereas FoxO1 was recently found to negatively regulate transcription of HuD under low glucose conditions in pancreatic β cells (Lee et al. 2012).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Lee et al. 2012
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Self-citation
- Authors
- Lee, E. K., Kim, W., Tominaga, K., Martindale, J. L., Yang, X., Subaran, S. S., Carlson, O. D., Mercken, E. M., Kulkarni, R. N., Akamatsu, W., Okano, H., Perrone-Bizzozero, N. I., de Cabo, R., Egan, J. M., & Gorospe, M.
- Affiliations
- National Institutes of Health (US)
- Joslin Diabetes Center (US)
- Keio University (JP)
- Corresponding author
- Gorospe, Myriam
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 45
- Issue
- 6
- Pages
- 826-835
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3319250
- OpenAlex
- W2101902163
- Cited by
- 108
- References
- 1
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 3 · 2023: 5 · 2022: 9 · 2021: 8 · 2020: 9 · 2019: 8 · 2018: 10 · 2017: 5 · 2016: 6 · 2015: 8 · 2014: 7 · 2013: 14 · 2012: 6
- FWCI
- 11.43
- Type
- journal article
- Language
- en
- Update notices
- erratum (2020-12-17)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (68721)
- Japan Society for the Promotion of Science (23618010)
- National Institute on Aging (ZIAAG000393)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK-67536, R01DK067536)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- HUD, RNA-binding proteins, pancreatic beta cells, 5' untranslated region, insulin receptor signaling, preproinsulin, insulin biosynthesis, glucose stimulation
- MeSH terms
- ELAV-Like Protein 4, Animals, Glucose, Humans, Insulin, Mice, Inbred C57BL, Mice, Transgenic, Protein Precursors, Protein Biosynthesis, Mice, Knockout, 5' Untranslated Regions, Insulin-Secreting Cells, Mice, ELAV Proteins
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