Auto- and cross-regulation of the hnRNP L proteins by alternative splicing.
Article Details
- CitationCopy to clipboard
Rossbach O, Hung LH, Schreiner S, Grishina I, Heiner M, Hui J, Bindereif A
Auto- and cross-regulation of the hnRNP L proteins by alternative splicing.
Mol Cell Biol. 2009 Mar;29(6):1442-51. doi: 10.1128/MCB.01689-08. Epub 2009 Jan 5.
- PubMed ID
- 19124611 [ View in PubMed]
- Abstract
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.