HnRNP L and HnRNP LL Antagonistically Modulate PTB-mediated Splicing Suppression of CHRNA1 Pre-mRNA

Overview

Journal Sci Rep

Specialty Science

Date 2013 Oct 15

PMID 24121633

Citations 23

Authors

Mohammad Alinoor Rahman

Akio Masuda

Kenji Ohe

Mikako Ito

David O Hutchinson

Akila Mayeda

Andrew G Engel

Kinji Ohno

Affiliations

Soon will be listed here.

Abstract

CHRNA1 gene, encoding the muscle nicotinic acetylcholine receptor alpha subunit, harbors an inframe exon P3A. Inclusion of exon P3A disables assembly of the acetylcholine receptor subunits. A single nucleotide mutation in exon P3A identified in congenital myasthenic syndrome causes exclusive inclusion of exon P3A. The mutation gains a de novo binding affinity for a splicing enhancing RNA-binding protein, hnRNP LL, and displaces binding of a splicing suppressing RNA-binding protein, hnRNP L. The hnRNP L binds to another splicing repressor PTB through the proline-rich region and promotes PTB binding to the polypyrimidine tract upstream of exon P3A, whereas hnRNP LL lacking the proline-rich region cannot bind to PTB. Interaction of hnRNP L with PTB inhibits association of U2AF(65) and U1 snRNP with the upstream and downstream of P3A, respectively, which causes a defect in exon P3A definition. HnRNP L and hnRNP LL thus antagonistically modulate PTB-mediated splicing suppression of exon P3A.

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References

Hahm B, Kim Y, Kim J, Kim T, Jang S . Heterogeneous nuclear ribonucleoprotein L interacts with the 3' border of the internal ribosomal entry site of hepatitis C virus. J Virol. 1998; 72(11):8782-8. PMC: 110294. DOI: 10.1128/JVI.72.11.8782-8788.1998. View

Andreetta F, Baggi F, Antozzi C, Torchiana E, Bernasconi P, Simoncini O . Acetylcholine receptor alpha-subunit isoforms are differentially expressed in thymuses from myasthenic patients. Am J Pathol. 1997; 150(1):341-8. PMC: 1858538. View

Kashima T, Rao N, David C, Manley J . hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing. Hum Mol Genet. 2007; 16(24):3149-59. DOI: 10.1093/hmg/ddm276. View

Krull M, Petrusma M, Makalowski W, Brosius J, Schmitz J . Functional persistence of exonized mammalian-wide interspersed repeat elements (MIRs). Genome Res. 2007; 17(8):1139-45. PMC: 1933517. DOI: 10.1101/gr.6320607. View

Gorlov I, Gorlova O, Frazier M, Amos C . Missense mutations in hMLH1 and hMSH2 are associated with exonic splicing enhancers. Am J Hum Genet. 2003; 73(5):1157-61. PMC: 1180494. DOI: 10.1086/378819. View

Ohno K, Wang H, Milone M, Bren N, Brengman J, Nakano S . Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor epsilon subunit. Neuron. 1996; 17(1):157-70. DOI: 10.1016/s0896-6273(00)80289-5. View

Chiou N, Shankarling G, Lynch K . hnRNP L and hnRNP A1 induce extended U1 snRNA interactions with an exon to repress spliceosome assembly. Mol Cell. 2013; 49(5):972-82. PMC: 3595347. DOI: 10.1016/j.molcel.2012.12.025. View

Masuda A, Shen X, Ito M, Matsuura T, Engel A, Ohno K . hnRNP H enhances skipping of a nonfunctional exon P3A in CHRNA1 and a mutation disrupting its binding causes congenital myasthenic syndrome. Hum Mol Genet. 2008; 17(24):4022-35. PMC: 2638575. DOI: 10.1093/hmg/ddn305. View

Goehe R, Shultz J, Murudkar C, Usanovic S, Lamour N, Massey D . hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing. J Clin Invest. 2010; 120(11):3923-39. PMC: 2964989. DOI: 10.1172/JCI43552. View

10.

Yan H, Papadopoulos N, Marra G, Perrera C, Jiricny J, Boland C . Conversion of diploidy to haploidy. Nature. 2000; 403(6771):723-4. DOI: 10.1038/35001659. View

11.

Duclert A, Savatier N, Schaeffer L, Changeux J . Identification of an element crucial for the sub-synaptic expression of the acetylcholine receptor epsilon-subunit gene. J Biol Chem. 1996; 271(29):17433-8. DOI: 10.1074/jbc.271.29.17433. View

12.

Engel A, Ohno K, Sine S . Sleuthing molecular targets for neurological diseases at the neuromuscular junction. Nat Rev Neurosci. 2003; 4(5):339-52. DOI: 10.1038/nrn1101. View

13.

Tong A, Nguyen J, Lynch K . Differential expression of CD45 isoforms is controlled by the combined activity of basal and inducible splicing-regulatory elements in each of the variable exons. J Biol Chem. 2005; 280(46):38297-304. DOI: 10.1074/jbc.M508123200. View

14.

Preussner M, Schreiner S, Hung L, Porstner M, Jack H, Benes V . HnRNP L and L-like cooperate in multiple-exon regulation of CD45 alternative splicing. Nucleic Acids Res. 2012; 40(12):5666-78. PMC: 3384337. DOI: 10.1093/nar/gks221. View

15.

Cartegni L, Hastings M, Calarco J, de Stanchina E, Krainer A . Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2. Am J Hum Genet. 2005; 78(1):63-77. PMC: 1380224. DOI: 10.1086/498853. View

16.

Kashima T, Manley J . A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nat Genet. 2003; 34(4):460-3. DOI: 10.1038/ng1207. View

17.

Pan Q, Shai O, Lee L, Frey B, Blencowe B . Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008; 40(12):1413-5. DOI: 10.1038/ng.259. View

18.

Spellman R, Smith C . Novel modes of splicing repression by PTB. Trends Biochem Sci. 2006; 31(2):73-6. DOI: 10.1016/j.tibs.2005.12.003. View

19.

Sharma S, Maris C, Allain F, Black D . U1 snRNA directly interacts with polypyrimidine tract-binding protein during splicing repression. Mol Cell. 2011; 41(5):579-88. PMC: 3931528. DOI: 10.1016/j.molcel.2011.02.012. View

20.

Clower C, Chatterjee D, Wang Z, Cantley L, Vander Heiden M, Krainer A . The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci U S A. 2010; 107(5):1894-9. PMC: 2838216. DOI: 10.1073/pnas.0914845107. View