Inefficient recruitment of DDX39B impedes pre-spliceosome assembly on FOXP3 introns.

Autor: Nagasawa CK; Human Pathophysiology and Translational Medicine Program, Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas 77550, USA.; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77550, USA.; Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA., Bailey AO; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77550, USA., Russell WK; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77550, USA., Garcia-Blanco MA; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77550, USA marianogb@virginia.edu.; Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA.
Jazyk: angličtina
Zdroj: RNA (New York, N.Y.) [RNA] 2024 Jun 17; Vol. 30 (7), pp. 824-838. Date of Electronic Publication: 2024 Jun 17.
DOI: 10.1261/rna.079933.123
Abstrakt: Forkhead box P3 (FOXP3) is the master fate-determining transcription factor in regulatory T (T reg ) cells and is essential for their development, function, and homeostasis. Mutations in FOXP3 cause immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, and aberrant expression of FOXP3 has been implicated in other diseases such as multiple sclerosis and cancer. We previously demonstrated that pre-mRNA splicing of FOXP3 RNAs is highly sensitive to levels of DExD-box polypeptide 39B (DDX39B), and here we investigate the mechanism of this sensitivity. FOXP3 introns have cytidine (C)-rich/uridine (U)-poor polypyrimidine (py) tracts that are responsible for their inefficient splicing and confer sensitivity to DDX39B. We show that there is a deficiency in the assembly of commitment complexes (CCs) on FOXP3 introns, which is consistent with the lower affinity of U2AF2 for C-rich/U-poor py tracts. Our data indicate an even stronger effect on the conversion of CCs to pre-spliceosomes. We propose that this is due to an altered conformation that U2AF2 adopts when it binds to C-rich/U-poor py tracts and that this conformation has a lower affinity for DDX39B. As a consequence, CCs assembled on FOXP3 introns are defective in recruiting DDX39B, and this leads to the inefficient assembly of pre-spliceosome complexes.
(© 2024 Nagasawa et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)
Databáze: MEDLINE
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