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Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6.

Interleukin 7 receptor, IL7R, is expressed exclusively on cells of the lymphoid lineage, and its expression is crucial for the development and maintenance of T cells. Alternative splicing of IL7R exon 6 results in membrane-bound (exon 6 included) and soluble (exon 6 skipped) IL7R isoforms. Interestingly, the inclusion of exon 6 is affected by a single-nucleotide polymorphism associated with the risk of developing multiple sclerosis. Given the potential association of exon 6 inclusion with multiple sclerosis, we investigated the cis-acting elements and trans-acting factors that regulate exon 6 splicing. We identified multiple exonic and intronic cis-acting elements that impact inclusion of exon 6. Moreover, we utilized RNA affinity chromatography followed by mass spectrometry to identify trans-acting protein factors that bind exon 6 and regulate its splicing. These experiments identified cleavage and polyadenylation specificity factor 1 (CPSF1) among protein-binding candidates. A consensus polyadenylation signal AAUAAA is present in intron 6 of IL7R directly downstream from the 5' splice site. Mutations to this site and CPSF1 knockdown both resulted in an increase in exon 6 inclusion. We found no evidence that this site is used to produce cleaved and polyadenylated mRNAs, suggesting that CPSF1 interaction with intronic IL7R pre-mRNA interferes with spliceosome binding to the exon 6 5' splice site. Our results suggest that competing mRNA splicing and polyadenylation regulate exon 6 inclusion and consequently determine the ratios of soluble to membrane-bound IL7R. This may be relevant for both T cell ontogeny and function and development of multiple sclerosis.

Pubmed ID: 23151878


  • Evsyukova I
  • Bradrick SS
  • Gregory SG
  • Garcia-Blanco MA


RNA (New York, N.Y.)

Publication Data

January 19, 2013

Associated Grants

  • Agency: NINDS NIH HHS, Id: 5R01-NS060925
  • Agency: NINDS NIH HHS, Id: R01 NS060925

Mesh Terms

  • Alternative Splicing
  • Animals
  • Cell Line
  • Chromatography, Affinity
  • Cleavage And Polyadenylation Specificity Factor
  • Exons
  • Gene Silencing
  • Humans
  • Introns
  • Mass Spectrometry
  • Multiple Sclerosis
  • Mutation
  • Polymorphism, Single Nucleotide
  • Protein Isoforms
  • RNA Splice Sites
  • RNA, Messenger
  • Rats
  • Receptors, Interleukin-7
  • Spliceosomes
  • Trans-Activators