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

Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 9509184 Publication Model: Electronic Cited Medium: Internet ISSN: 1469-9001 (Electronic) Linking ISSN: 13558382 NLM ISO Abbreviation: RNA Subsets: MEDLINE

Publication: <2003->: Cold Spring Harbor, NY : Cold Spring Harbor Laboratory Press
Original Publication: New York, NY : Cambridge University Press, c1995-

DEAD-box RNA Helicases*/genetics ; DEAD-box RNA Helicases*/metabolism ; Introns* ; Forkhead Transcription Factors*/genetics ; Forkhead Transcription Factors*/metabolism ; Spliceosomes*/metabolism ; Spliceosomes*/genetics ; RNA Splicing*; Humans ; RNA Precursors/genetics ; RNA Precursors/metabolism

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.)

Cell. 1983 Jun;33(2):509-18. (PMID: 6190573)
Science. 1996 Sep 20;273(5282):1706-9. (PMID: 8781232)
Nucleic Acids Res. 2024 May 27;:. (PMID: 38801080)
Cold Spring Harb Perspect Biol. 2019 Nov 1;11(11):. (PMID: 30765414)
Gene Anal Tech. 1988 Mar-Apr;5(2):22-31. (PMID: 3192155)
RNA Biol. 2021 Dec;18(12):2576-2593. (PMID: 34105434)
Genes Dev. 1991 Jul;5(7):1224-36. (PMID: 1906035)
Nat Genet. 2007 Jul;39(7):857-64. (PMID: 17554260)
Cell. 2017 Mar 23;169(1):72-84.e13. (PMID: 28340352)
Cell Cycle. 2016 Dec 16;15(24):3362-3377. (PMID: 27792457)
Nucleic Acids Res. 2022 May 20;50(9):5299-5312. (PMID: 35524551)
Genes Dev. 1991 Dec;5(12B):2534-46. (PMID: 1836445)
Proc Natl Acad Sci U S A. 2013 May 7;110(19):E1761-70. (PMID: 23610432)
Genes Dev. 1997 Jul 15;11(14):1864-72. (PMID: 9242493)
Cell. 1985 May;41(1):95-105. (PMID: 3888410)
Mol Cell. 2006 Jul 7;23(1):49-59. (PMID: 16818232)
J Rheumatol. 2008 May;35(5):741-4. (PMID: 18381799)
Cell. 1993 Dec 17;75(6):1061-70. (PMID: 8261509)
Genes Dev. 2001 Jan 1;15(1):42-9. (PMID: 11156604)
J Biol Chem. 1993 May 25;268(15):11222-9. (PMID: 8496178)
Genes Dev. 2001 Jan 1;15(1):30-5. (PMID: 11156602)
Genes Dev. 2008 Jul 1;22(13):1796-803. (PMID: 18593880)
J Clin Immunol. 2019 Oct;39(7):623-640. (PMID: 31478130)
Nucleic Acids Res. 1983 Mar 11;11(5):1475-89. (PMID: 6828386)
Science. 1989 Jan 13;243(4888):214-7. (PMID: 2911734)
Genes Dev. 1998 Mar 15;12(6):858-67. (PMID: 9512519)
Nature. 1992 Feb 13;355(6361):609-14. (PMID: 1538748)
Mol Biol Cell. 2010 Aug 15;21(16):2953-65. (PMID: 20573985)
Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17420-5. (PMID: 25422459)
Proc Natl Acad Sci U S A. 1979 Nov;76(11):5495-9. (PMID: 316537)
Cell. 1987 Jun 19;49(6):763-74. (PMID: 2953438)
Genes Dev. 2000 Jan 1;14(1):97-107. (PMID: 10640279)
Nature. 1994 Mar 10;368(6467):119-24. (PMID: 8139654)
Nat Genet. 2011 Dec 25;44(2):187-92. (PMID: 22197932)
EMBO J. 1994 Jul 15;13(14):3356-67. (PMID: 8045264)
Methods Mol Biol. 2004;257:47-64. (PMID: 14769995)
Nature. 2002 May 16;417(6886):304-8. (PMID: 11979277)
Nature. 2001 Oct 11;413(6856):644-7. (PMID: 11675789)
Genes Dev. 2005 Jul 1;19(13):1512-7. (PMID: 15998806)
Cold Spring Harb Perspect Biol. 2011 Jul 01;3(7):. (PMID: 21441581)
Mol Cell. 2000 May;5(5):779-87. (PMID: 10882114)
Mol Cell Biol. 1998 Aug;18(8):4752-60. (PMID: 9671485)
Cell. 1997 May 2;89(3):403-12. (PMID: 9150140)
Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5482-6. (PMID: 1535158)
Genes Dev. 2015 Jan 1;29(1):81-93. (PMID: 25561497)
Nature. 2021 Aug;596(7871):296-300. (PMID: 34349264)
J Biol Chem. 2007 Aug 3;282(31):22544-50. (PMID: 17562711)
Nature. 1980 Jan 10;283(5743):220-4. (PMID: 7350545)
Mol Cell Biol. 1992 Oct;12(10):4279-87. (PMID: 1383687)
Genes Cells. 2001 May;6(5):487-94. (PMID: 11380625)
Nature. 2011 Jul 13;475(7356):408-11. (PMID: 21753750)
Nucleic Acids Res. 2013 Apr 1;41(6):3859-73. (PMID: 23376934)
Elife. 2023 Jun 01;12:. (PMID: 37261960)

P01 AI150585 United States AI NIAID NIH HHS

Keywords: DDX39B; FOXP3; IPEX syndrome; autoimmunity; multiple sclerosis; pre-mRNA splicing

EC 3.6.4.13 (DEAD-box RNA Helicases)
0 (Forkhead Transcription Factors)
EC 3.6.1.- (DDX39B protein, human)
0 (FOXP3 protein, human)
0 (RNA Precursors)

Date Created: 20240404 Date Completed: 20240617 Latest Revision: 20240702

20240702

PMC11182011

10.1261/rna.079933.123

38575347