Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization

Rie Murayama, Mariko Kimura-Asami, Marina Togo-Ohno, Yumiko Yamasaki-Kato, Taeko K. Naruse, Takeshi Yamamoto, Takeharu Hayashi, Tomohiko Ai, Katherine G. Spoonamore, Richard Kovacs, Matteo Vatta, Mai Iizuka, Masumi Saito, Shotaro Wani, Yuichi Hiraoka, Akinori Kimura, Hidehito Kuroyanagi

Research output: Contribution to journalArticle

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Abstract

RBM20 is a major regulator of heart-specific alternative pre-mRNA splicing of TTN encoding a giant sarcomeric protein titin. Mutation in RBM20 is linked to autosomal-dominant familial dilated cardiomyopathy (DCM), yet most of the RBM20 missense mutations in familial and sporadic cases were mapped to an RSRSP stretch in an arginine/serine-rich region of which function remains unknown. In the present study, we identified an R634W missense mutation within the stretch and a G1031X nonsense mutation in cohorts of DCM patients. We demonstrate that the two serine residues in the RSRSP stretch are constitutively phosphorylated and mutations in the stretch disturb nuclear localization of RBM20. Rbm20 S637A knock-in mouse mimicking an S635A mutation reported in a familial case showed a remarkable effect on titin isoform expression like in a patient carrying the mutation. These results revealed the function of the RSRSP stretch as a critical part of a nuclear localization signal and offer the Rbm20 S637A mouse as a good model for in vivo study.

Original languageEnglish (US)
Article number8970
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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RNA-Binding Proteins
Phosphorylation
Connectin
Mutation
Missense Mutation
Serine
Nuclear RNA
Nuclear Localization Signals
Nonsense Codon
RNA Precursors
Dilated Cardiomyopathy
Arginine
Protein Isoforms
RNA-Binding Motifs
Proteins

ASJC Scopus subject areas

  • General

Cite this

Murayama, R., Kimura-Asami, M., Togo-Ohno, M., Yamasaki-Kato, Y., Naruse, T. K., Yamamoto, T., ... Kuroyanagi, H. (2018). Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization. Scientific Reports, 8(1), [8970]. https://doi.org/10.1038/s41598-018-26624-w

Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization. / Murayama, Rie; Kimura-Asami, Mariko; Togo-Ohno, Marina; Yamasaki-Kato, Yumiko; Naruse, Taeko K.; Yamamoto, Takeshi; Hayashi, Takeharu; Ai, Tomohiko; Spoonamore, Katherine G.; Kovacs, Richard; Vatta, Matteo; Iizuka, Mai; Saito, Masumi; Wani, Shotaro; Hiraoka, Yuichi; Kimura, Akinori; Kuroyanagi, Hidehito.

In: Scientific Reports, Vol. 8, No. 1, 8970, 01.12.2018.

Research output: Contribution to journalArticle

Murayama, R, Kimura-Asami, M, Togo-Ohno, M, Yamasaki-Kato, Y, Naruse, TK, Yamamoto, T, Hayashi, T, Ai, T, Spoonamore, KG, Kovacs, R, Vatta, M, Iizuka, M, Saito, M, Wani, S, Hiraoka, Y, Kimura, A & Kuroyanagi, H 2018, 'Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization', Scientific Reports, vol. 8, no. 1, 8970. https://doi.org/10.1038/s41598-018-26624-w
Murayama, Rie ; Kimura-Asami, Mariko ; Togo-Ohno, Marina ; Yamasaki-Kato, Yumiko ; Naruse, Taeko K. ; Yamamoto, Takeshi ; Hayashi, Takeharu ; Ai, Tomohiko ; Spoonamore, Katherine G. ; Kovacs, Richard ; Vatta, Matteo ; Iizuka, Mai ; Saito, Masumi ; Wani, Shotaro ; Hiraoka, Yuichi ; Kimura, Akinori ; Kuroyanagi, Hidehito. / Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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abstract = "RBM20 is a major regulator of heart-specific alternative pre-mRNA splicing of TTN encoding a giant sarcomeric protein titin. Mutation in RBM20 is linked to autosomal-dominant familial dilated cardiomyopathy (DCM), yet most of the RBM20 missense mutations in familial and sporadic cases were mapped to an RSRSP stretch in an arginine/serine-rich region of which function remains unknown. In the present study, we identified an R634W missense mutation within the stretch and a G1031X nonsense mutation in cohorts of DCM patients. We demonstrate that the two serine residues in the RSRSP stretch are constitutively phosphorylated and mutations in the stretch disturb nuclear localization of RBM20. Rbm20 S637A knock-in mouse mimicking an S635A mutation reported in a familial case showed a remarkable effect on titin isoform expression like in a patient carrying the mutation. These results revealed the function of the RSRSP stretch as a critical part of a nuclear localization signal and offer the Rbm20 S637A mouse as a good model for in vivo study.",
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