Auto- and Cross-Regulation of the hnRNP L Proteins by Alternative Splicing
Open accessAbstract
We recently characterized human hnRNP L as a global regulator of alternative splicing, binding to CA-repeat and CA-rich elements. Here we report that hnRNP L autoregulates its own expression on the level of alternative splicing. Intron 6 of the human hnRNP L gene contains a short exon that, if used, introduces a premature termination codon, resulting in nonsense-mediated decay (NMD). This "poison exon" is preceded by a highly conserved CA-rich cluster extending over 800 nucleotides that binds hnRNP L and functions as an unusually extended, intronic enhancer, promoting inclusion of the poison exon. As a result, excess hnRNP L activates NMD of its own mRNA, thereby creating a negative autoregulatory feedback loop and contributing to homeostasis of hnRNP L levels. We present experimental evidence for this mechanism, based on NMD inactivation, hnRNP L binding assays, and hnRNP L-dependent alternative splicing of heterologous constructs. In addition, we demonstrate that hnRNP L cross-regulates inclusion of an analogous poison exon in the hnRNP L-like pre-mRNA, which explains the reciprocal expression of the two closely related hnRNP L proteins.
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The mutually exclusive expression pattern of SLM1 and SLM2 is enforced by their cross-regulation via alternative splicing coupled with NMD.
“The mutually exclusive expression pattern of SLM1 and SLM2 is enforced by their cross-regulation via alternative splicing coupled with NMD, as seen with other paralogous pairs of RNA-binding proteins15,20,21,49,53,85,86.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [85]
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References 41 · Cited by 141
Research works printed but not linked: 2
- [7]Coutinho-Mansfield, G. C., Y. Xue, Y. Zhang, and X. D. Fu. 2007. PTB/nPTB switch: a posttranscriptional mechanism for programming neuronal differentiation. Genes Dev. 211573-1577. [DOI] [PubMed] [Google Scholar]
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- Authors
- Rossbach, O., Hung, L.-H., Schreiner, S., Grishina, I., Heiner, M., Hui, J., & Bindereif, A.
- Affiliations
- Chinese Academy of Sciences (CN)
- Corresponding author
- Bindereif, Albrecht
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2009-03-01
- Volume
- 29
- Issue
- 6
- Pages
- 1442-1451
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2648227
- OpenAlex
- W2148972157
- Cited by
- 141
- References
- 41
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 4 · 2023: 11 · 2022: 7 · 2021: 8 · 2020: 20 · 2019: 7 · 2018: 7 · 2017: 9 · 2016: 10 · 2015: 6 · 2014: 9 · 2013: 10 · 2012: 5
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- hnRNP L, alternative splicing, nonsense-mediated mRNA decay, poison exon, intronic enhancer, autoregulation, negative feedback loop, proteostasis, intron 6
- MeSH terms
- Enhancer Elements, Genetic, Exons, Gene Expression Regulation, HeLa Cells, Humans, Introns, Nucleic Acid Conformation, RNA Precursors, Alternative Splicing, Heterogeneous-Nuclear Ribonucleoprotein L
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