Context-Dependent Regulatory Mechanism of the Splicing Factor hnRNP L

• Published in: Molecular cell Vol. 37; no. 2; pp. 223 - 234
• Main Authors: Motta-Mena, Laura B., Heyd, Florian, Lynch, Kristen W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.01.2010
• Subjects: CD45 antigen; Exons; Heterogeneous-Nuclear Ribonucleoprotein L - physiology; Humans; Leukocyte Common Antigens - chemistry; Leukocyte Common Antigens - genetics; Leukocyte Common Antigens - metabolism; Models, Genetic; PROTEINS; RNA; RNA Splice Sites; RNA Splicing; RNA; PROTEINS
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2009.12.027

Splicing regulatory proteins often have distinct activities when bound to exons versus introns. However, less clear is whether variables aside from location can influence activity. HnRNP L binds to a motif present in both CD45 variable exons 4 and 5 to affect their coordinate repression. Here, we show that, in contrast to its direct repression of exon 4, hnRNP L represses exon 5 by countering the activity of a neighboring splicing enhancer. In the absence of the enhancer, hnRNP L unexpectedly activates exon inclusion. As the splice sites flanking exon 4 and 5 are distinct, we directly examined the effect of varying splice site strength on the mechanism of hnRNP L function. Remarkably, binding of hnRNP L to an exon represses strong splice sites but enhances weak splice sites. A model in which hnRNP L stabilizes snRNP binding can explain both effects in a manner determined by the inherent snRNP-substrate affinity. [Display omitted] ► Coordinate regulation of CD45 exons 4 and 5 by hnRNP L occurs by distinct mechanisms ► HnRNP L represses CD45 exon 5 by competing with binding of SF2/ASF to an ESE ► HnRNP L can have enhancer or repressor activities when bound to an exon ► Weakening of splice site strength flips hnRNP L from an exon repressor to an activator