Distant coupling between RNA editing and alternative splicing of the osmosensitive cation channel Tmem63b

Abstract

Post-transcriptional modifications of pre-mRNAs expand the diversity of proteomes in higher eukaryotes. In the brain, these modifications diversify the functional output of many critical neuronal signal molecules. In this study, we identified a brain-specific A-to-I RNA editing that changed glutamine to arginine (Q/R) at exon 20 and an alternative splicing of exon 4 in Tmem63b, which encodes a ubiquitously expressed osmosensitive cation channel. The channel isoforms lacking exon 4 occurred in ∼80% of Tmem63b mRNAs in the brain but were not detected in other tissues, suggesting a brain-specific splicing. We found that the Q/R editing was catalyzed by Adar2 (Adarb1) and required an editing site complementary sequence located in the proximal 5′ end of intron 20. Moreover, the Q/R editing was almost exclusively identified in the splicing isoform lacking exon 4, indicating a coupling between the editing and the splicing. Elimination of the Q/R editing in brain-specific Adar2 knockout mice did not affect the splicing efficiency of exon 4. Furthermore, transfection with the splicing isoform containing exon 4 suppressed the Q/R editing in primary cultured cerebellar granule neurons. Thus, our study revealed a coupling between an RNA editing and a distant alternative splicing in the Tmem63b pre-mRNA, in which the splicing plays a dominant role. Finally, physiological analysis showed that the splicing and the editing coordinately regulate Ca2+ permeability and osmosensitivity of channel proteins, which may contribute to their functions in the brain. Post-transcriptional modifications of pre-mRNAs expand the diversity of proteomes in higher eukaryotes. In the brain, these modifications diversify the functional output of many critical neuronal signal molecules. In this study, we identified a brain-specific A-to-I RNA editing that changed glutamine to arginine (Q/R) at exon 20 and an alternative splicing of exon 4 in Tmem63b, which encodes a ubiquitously expressed osmosensitive cation channel. The channel isoforms lacking exon 4 occurred in ∼80% of Tmem63b mRNAs in the brain but were not detected in other tissues, suggesting a brain-specific splicing. We found that the Q/R editing was catalyzed by Adar2 (Adarb1) and required an editing site complementary sequence located in the proximal 5′ end of intron 20. Moreover, the Q/R editing was almost exclusively identified in the splicing isoform lacking exon 4, indicating a coupling between the editing and the splicing. Elimination of the Q/R editing in brain-specific Adar2 knockout mice did not affect the splicing efficiency of exon 4. Furthermore, transfection with the splicing isoform containing exon 4 suppressed the Q/R editing in primary cultured cerebellar granule neurons. Thus, our study revealed a coupling between an RNA editing and a distant alternative splicing in the Tmem63b pre-mRNA, in which the splicing plays a dominant role. Finally, physiological analysis showed that the splicing and the editing coordinately regulate Ca2+ permeability and osmosensitivity of channel proteins, which may contribute to their functions in the brain. RNA editing is a post-transcriptional modification of pre-mRNAs that can introduce codon changes in mature mRNAs. The A (adenosine)-to-I (inosine) deamination in pre-mRNAs is the most abundant RNA editing in mammals (1Tan M.H. Li Q. Shanmugam R. Piskol R. Kohler J. Young A.N. Liu K.I. Zhang R. Ramaswami G. Ariyoshi K. Gupte A. Keegan L.P. George C.X. Ramu A. Huang N. et al.Dynamic landscape and regulation of RNA editing in mammals.Nature. 2017; 550 (29022589): 249-25410.1038/nature24041Crossref PubMed Scopus (215) Google Scholar). Because inosine in mRNA is interpreted as guanosine (G) during translation (2Basilio C. Wahba A.J. Lengyel P. Speyer J.F. Ochoa S. Synthetic polynucleotides and the amino acid code. V.Proc. Natl. Acad. Sci. U. S. A. 1962; 48 (13865603): 613-61610.1073/pnas.48.4.613Crossref PubMed Scopus (125) Google Scholar), the A-to-I editing often leads to changes in amino acid sequence. The A-to-I editing occurs in important signal molecules, including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA2 subunit (3Sommer B. Köhler M. Sprengel R. Seeburg P.H. RNA editing in brain controls a determinant of ion flow in glutamate-gated channels.Cell. 1991; 67 (1717158): 11-1910.1016/0092-8674(91)90568-JAbstract Full Text PDF PubMed Scopus (1122) Google Scholar), kainate receptor GluK1 and GluK2 subunits (4Köhler M. Burnashev N. Sakmann B. Seeburg P.H. Determinants of Ca2+ permeability in both TM1 and TM2 of high affinity kainate receptor channels: diversity by RNA editing.Neuron. 1993; 10 (7681676): 491-50010.1016/0896-6273(93)90336-PAbstract Full Text PDF PubMed Scopus (348) Google Scholar), Kv1.1 α subunit, and 5-HT2C receptors (5Hoopengardner B. Bhalla T. Staber C. Reenan R. Nervous system targets of RNA editing identified by comparative genomics.Science. 2003; 301 (12907802): 832-83610.1126/science.1086763Crossref PubMed Scopus (321) Google Scholar, 6Burns C.M. Chu H. Rueter S.M. Hutchinson L.K. Canton H. Sanders-Bush E. Emeson R.B. Regulation of serotonin-2C receptor G-protein coupling by RNA editing.Nature. 1997; 387 (9153397): 303-30810.1038/387303a0Crossref PubMed Scopus (825) Google Scholar), which are known to regulate neuronal development, circuit formation, neuronal degeneration, and M. M. RNA A to neuronal in the Full Text Full Text PDF PubMed Scopus Google Scholar, receptors in and neuronal Full Text Full Text PDF PubMed Scopus Google Scholar, H. C. receptors containing to J. PubMed Scopus Google Scholar, P. Liu S. Liu RNA editing of receptor subunit of in Full Text Full Text PDF PubMed Scopus Google Scholar). The A-to-I editing is catalyzed by which the by the editing and the editing site complementary sequence and the to inosine M. Köhler M. B. Sprengel R. Seeburg P.H. RNA editing of receptor subunit a and 1993; Full Text PDF PubMed Scopus Google Scholar). In and Adar2 (Adarb1) (1Tan M.H. Li Q. Shanmugam R. Piskol R. Kohler J. Young A.N. Liu K.I. Zhang R. Ramaswami G. Ariyoshi K. Gupte A. Keegan L.P. George C.X. Ramu A. Huang N. et al.Dynamic landscape and regulation of RNA editing in mammals.Nature. 2017; 550 (29022589): 249-25410.1038/nature24041Crossref PubMed Scopus (215) Google Scholar). splicing is of post-transcriptional modification of pre-mRNAs in of the by alternative PubMed Scopus Google Scholar). of alternative splicing in in Q. of alternative splicing in the by PubMed Scopus Google Scholar, R. S. Zhang C. isoform regulation in PubMed Scopus Google Scholar). alternative splicing is in including R. T. and RNA splicing in PubMed Scopus Google Scholar), H. M. E. and alternative splicing of in of mice and with Full Text Full Text PDF PubMed Scopus Google Scholar, T. Li G. J. M. S. B. T. S. Zhang B. P. et of the brain splicing in PubMed Scopus Google Scholar), T. A in exon splicing in 2003; PubMed Scopus Google Scholar), J. B. Li S. A. R. R. et in in and and PubMed Scopus Google Scholar, B. T. C. S. S. splicing of and PubMed Scopus Google Scholar), and H. splicing in regulation to PubMed Scopus Google Scholar). the A-to-I RNA editing in and the alternative splicing of are often the editing at exon of alternative splicing of exon and exon A. of receptor Q/R editing coupling to editing and PubMed Scopus Google Scholar, S. Regulation of receptor splicing by RNA PubMed Scopus Google Scholar, E. M. of editing and splicing of receptor 2003; PubMed Scopus Google Scholar). The splicing efficiency editing is by K. U. E. to inosine editing by splicing PubMed Scopus Google Scholar, K. U. E. P. A high A-to-I editing in the editing by PubMed Scopus Google Scholar). We found that Tmem63b as an in the and is required of and H. C. Zhang C. P. G. The cation channel is an required Full Text Full Text PDF PubMed Scopus Google Scholar). expand our of Tmem63b functions in other we Tmem63b mRNA brain in the We identified isoforms of Tmem63b an A-to-I RNA editing that changes glutamine to arginine at exon 20 and an alternative splicing of exon 4. The editing was almost exclusively detected in the isoform lacking exon 4, suggesting a between the post-transcriptional Adar2 mice and cultured cerebellar granule we found that the isoform containing exon 4 suppressed the Q/R editing efficiency in a analysis that the splicing and the editing coordinately Ca2+ these a coupling between alternative RNA splicing and RNA editing in Tmem63b, in which the splicing plays a dominant role. post-transcriptional modifications may the osmosensitive Tmem63b channel to in the brain. the osmosensitive cation in H. C. Zhang C. P. G. The cation channel is an required Full Text Full Text PDF PubMed Scopus Google Scholar, A. A. M. A. B. A. T. A. E. et of the of a in to PubMed Scopus Google Scholar, H. G. H. J. T. J. A. A. Li et in the ion channel in during J. Full Text Full Text PDF PubMed Scopus Google Scholar). Tmem63b brain tissues, we sequence that was the mRNA sequence in the The in this was of the at the site in exon 20. an A-to-I RNA editing that in the of glutamine codon to arginine codon at of the sequence In exon 4 was in the Thus, the Tmem63b we was a isoform with post-transcriptional A-to-I editing at in exon 20 and alternative splicing of exon 4. The of A to at the site an site were to containing the editing site and brain The of brain of mice were by and showed and the were not by to Tmem63b other brain, including and suggesting that this editing is In the editing efficiency in brain in the to in other brain in mice and A and editing was during the development, we the Q/R editing in and and and editing efficiency as with the and and was editing in the of of of at this (1Tan M.H. Li Q. Shanmugam R. Piskol R. Kohler J. Young A.N. Liu K.I. Zhang R. Ramaswami G. Ariyoshi K. Gupte A. Keegan L.P. George C.X. Ramu A. Huang N. et al.Dynamic landscape and regulation of RNA editing in mammals.Nature. 2017; 550 (29022589): 249-25410.1038/nature24041Crossref PubMed Scopus (215) Google Scholar). brain at were in the brain and A and In and Adar2 (Adarb1) A-to-I Adar2 catalyzed the Q/R editing in Tmem63b, we Adar2 with a Tmem63b containing the sequence exon to exon editing in and the editing efficiency Tmem63b in the were by a to sequence Adar2 but not transfection in of and by that the was we with an containing the editing site at exon that is by M. A. M. K. M. of an RNA of A-to-I RNA editing 20 PubMed Scopus Google and found that this site was the Tmem63b Q/R editing was catalyzed by Adar2 in we Adar2 mice and with C. P. K. R. R. G. of the receptor in the system in PubMed Scopus Google to brain-specific Adar2 mice The Adar2 mice were of to the Q/R site M. S. J. A. Burnashev N. Sprengel R. Seeburg P.H. in an receptor in mice in the PubMed Scopus Google Scholar). We the Q/R editing of Tmem63b in The Q/R editing of Tmem63b was in Adar2 and the critical Q/R editing of Tmem63b, we the of RNA sequence editing site the RNA and PubMed Scopus Google Scholar). A containing Q/R editing site was and the sequence to the editing was as We a of the and their Q/R editing in Adar2 The editing efficiency in sequence was of the of Q/R editing In that the the editing efficiency of the the editing site the editing efficiency indicating the of the by the and the editing the sequence at the proximal 5′ end of intron 20 was to the Q/R study alternative splicing of exon 4, a of and were to the sequence exon 4 Tmem63b with exon 4 were of and The efficiency of the splicing was as the of to The was detected in brain of but not in and a splicing occurred in of Tmem63b mRNAs. In the ∼80% of the Tmem63b mRNAs were the The splicing efficiency in brain to and A and In the splicing efficiency in was to that in the but was in the and with the of Tmem63b mRNAs at that the splicing efficiency in Tmem63b was during and and and that to ∼80% of Tmem63b mRNAs brain were isoforms lacking exon 4. was that the this of isoform the an the splicing we of to the the and the Tmem63b and the splicing by The showed that the and the were and of the Tmem63b mRNAs that of mRNAs brain were the alternative splicing of Tmem63b exon 4 is The splicing efficiency is brain and at that A-to-I editing in and splicing of affect other A. of receptor Q/R editing coupling to editing and PubMed Scopus Google Scholar, S. Regulation of receptor splicing by RNA PubMed Scopus Google Scholar, E. M. of editing and splicing of receptor 2003; PubMed Scopus Google Scholar, K. U. E. to inosine editing by splicing PubMed Scopus Google Scholar, K. U. E. P. A high A-to-I editing in the editing by PubMed Scopus Google Scholar). the Q/R editing at exon 20 and the splicing of exon 4 in Tmem63b are Tmem63b brain were to with of which were lacking exon 4 and the of the at the Q/R In were not at the Q/R site that Q/R editing efficiency in and isoforms was We this A of with the to exon 4 and the of the Q/R site was to the isoform The with 4 of the end to exon and the of sequence to exon was to the isoform We found that the isoform were by and the were not in Tmem63b and The Q/R editing was to the mRNAs of and and indicating that coupling is during the editing efficiency in was in The editing efficiency in Tmem63b was in brain of and In the editing was in and ∼80% in other brain in the editing in mRNAs was in brain as with in and A and Q/R editing is the Tmem63b, we the Tmem63b and to In of the and were at the Q/R In of the the isoform were to at the Q/R site these that the alternative splicing of exon 4 and Q/R editing at exon 20 in Tmem63b were We which of the post-transcriptional the editing the was We that the editing the splicing efficiency as A. of receptor Q/R editing coupling to editing and PubMed Scopus Google Scholar, S. 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M. of editing and splicing of receptor 2003; PubMed Scopus Google Scholar), the alternative splicing of exon 4 in Adar2 we found that the efficiency of alternative splicing was not changed A and suggesting that the editing did not affect the splicing. the that the splicing the we primary of We the coupling of splicing and editing of Tmem63b in these at a at which we the The splicing efficiency was to that in the brain of mice The editing efficiency of Tmem63b in cultured was to that in the the editing was detected in isoforms with editing efficiency of and We the splicing and editing of Tmem63b in cultured The editing of Tmem63b was The alternative splicing the editing a the Tmem63b regulate the a the mRNA sequence the splicing the the Tmem63b, the are intron and intron 4 in the is We found that these the editing efficiency and a we by the editing with containing exon by alternative splicing of exon 4 and The sequence exon to exon with the editing was to The editing efficiency in was to with the editing but higher with the editing indicating that the splicing the editing in a We the editing efficiency can by splicing. 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A. are an of ion Scopus Google Scholar, M. C. C. of the PubMed Scopus Google Scholar, H. R. Li C. Zhang J. T. B. Ca2+ in PubMed Scopus Google Scholar). The of and revealed that are channel including ion and M. C. C. of the PubMed Scopus Google Scholar, S. K. A. of the ion channel PubMed Scopus Google Scholar, J. of the channel PubMed Scopus Google Scholar). the editing and splicing affect the channel we a Tmem63b the of S. K. A. of the ion channel PubMed Scopus Google Scholar). The Tmem63b Q/R site is located at the of the channel of A and A arginine at this with the of as this we the Ca2+ to these isoforms of Tmem63b in H. C. Zhang C. P. G. The cation channel is an required Full Text Full Text PDF PubMed Scopus Google Scholar). were a in by to and We the in both and was to the the H. C. Zhang C. P. G. The cation channel is an required Full Text Full Text PDF PubMed Scopus Google Scholar). The was by of the Tmem63b were by and the of at the was to Ca2+ Because most with to we did not to the at in this H. C. Zhang C. P. G. The cation channel is an required Full Text Full Text PDF PubMed Scopus Google Scholar). The in was isoform isoform isoform with the and isoform with the The in Ca2+ was and and The Ca2+ permeability to was that Q/R editing at the of Tmem63b channel Ca2+ The exon 4 of Tmem63b amino in the between and A and In the is to in S. K. A. of the ion channel PubMed Scopus Google Scholar, J. of the channel PubMed Scopus Google Scholar). We that are osmosensitive cation by and Ca2+ H. C. Zhang C. P. G. The cation channel is an required Full Text Full Text PDF PubMed Scopus Google Scholar). We that the most the osmosensitivity was the of to H. C. Zhang C. P. G. The cation channel is an required Full Text Full Text PDF PubMed Scopus Google Scholar). our of osmosensitivity is with the by a of in T. S. S.M. A. are an of ion Scopus Google Scholar), indicating that the osmosensitivity the we the osmosensitivity of the isoforms of Tmem63b this In we expressed Tmem63b isoforms with the in H. C. Zhang C. P. G. The cation channel is an required Full Text Full Text PDF PubMed Scopus Google Scholar). was the to The was detected in Tmem63b but the of isoforms that not Tmem63b to to Ca2+ occurred in the of Tmem63b of and of in the of and of indicating that of exon 4 the osmosensitivity of Tmem63b channel showed that to to Thus, the alternative splicing of exon 4 and the Q/R editing in Tmem63b coordinately regulate Ca2+ by In this study, we identified a coupling between the A-to-I editing at the Q/R site of exon 20 and the alternative splicing of exon 4 in Tmem63b pre-mRNAs in the brain. study that the the post-transcriptional modifications are the alternative RNA splicing plays a dominant role. In our of Tmem63b mRNAs are at the Q/R site in the brain, with a study P. C. S. J. R. of site PubMed Scopus Google Scholar). The that this RNA editing is brain-specific is with (1Tan M.H. Li Q. Shanmugam R. Piskol R. Kohler J. Young A.N. Liu K.I. Zhang R. Ramaswami G. Ariyoshi K. Gupte A. Keegan L.P. George C.X. Ramu A. Huang N. et al.Dynamic landscape and regulation of RNA editing in mammals.Nature. 2017; 550 (29022589): 249-25410.1038/nature24041Crossref PubMed Scopus (215) Google Scholar, N. S. M. Li J. E. in A-to-I RNA editing in with changes in 2017; PubMed Scopus Google Scholar, R. Zhang H. Liu K.I. Zhang M.H. editing of brain-specific in PubMed Scopus Google Scholar). Furthermore, we that the editing in brain at we that the editing in with (1Tan M.H. Li Q. Shanmugam R. Piskol R. Kohler J. Young A.N. Liu K.I. Zhang R. Ramaswami G. Ariyoshi K. Gupte A. Keegan L.P. George C.X. Ramu A. Huang N. et al.Dynamic landscape and regulation of RNA editing in mammals.Nature. 2017; 550 (29022589): 249-25410.1038/nature24041Crossref PubMed Scopus (215) Google Scholar, R. Zhang H. Liu K.I. Zhang M.H. editing of brain-specific in PubMed Scopus Google Scholar), and that the is at the proximal 5′ end of intron 20. We identified an alternative splicing of exon 4 in Tmem63b mRNAs. The Tmem63b mRNA isoform lacking exon 4 is the in the brain and of the Tmem63b mRNAs. The splicing efficiency is in brain and at the the alternative splicing occurs in the brain. the isoform of the Tmem63b mRNAs in the is not in other The Q/R editing and alternative splicing in Tmem63b are in which the alternative splicing of exon 4 plays a dominant role. that the A-to-I editing and the splicing of often affect other A. of receptor Q/R editing coupling to editing and PubMed Scopus Google Scholar, S. Regulation of receptor splicing by RNA PubMed Scopus Google Scholar, E. M. of editing and splicing of receptor 2003; PubMed Scopus Google Scholar, K. U. E. to inosine editing by splicing PubMed Scopus Google Scholar, K. U. E. P. A high A-to-I editing in the editing by PubMed Scopus Google Scholar). by between the editing and the that may the the our the between an A-to-I editing and a distant alternative splicing not analysis that the Q/R editing of Tmem63b Adar2 to the by and the editing of Adar2 the Q/R and the the editing and We that the splicing of exon 4 may regulate the of the editing affect Adar2 in to the that the of Adar2 and the editing R. J. S. A. S. N. A. Keegan L.P. G. and regulate Q/R site RNA editing by with J. PubMed Scopus Google Scholar). and regulate the of Adar2 to affect RNA editing (1Tan M.H. Li Q. Shanmugam R. Piskol R. Kohler J. Young A.N. Liu K.I. Zhang R. Ramaswami G. Ariyoshi K. Gupte A. Keegan L.P. George C.X. Ramu A. Huang N. et al.Dynamic landscape and regulation of RNA editing in mammals.Nature. 2017; 550 (29022589): 249-25410.1038/nature24041Crossref PubMed Scopus (215) Google Scholar, R. J. S. A. S. N. A. Keegan L.P. G. and regulate Q/R site RNA editing by with J. PubMed Scopus Google Scholar). The splicing RNA editing R. Zhang H. Liu K.I. Zhang M.H. editing of brain-specific in PubMed Scopus Google Scholar, H. K. S. K. of RNA editing of by splicing PubMed Scopus Google Scholar). the Tmem63b Q/R editing in the brain R. Zhang H. Liu K.I. Zhang M.H. editing of brain-specific in PubMed Scopus Google Scholar). Thus, is that the splicing of exon 4 the Q/R editing of the We that the exon 4 alternative splicing and the Q/R editing regulate the osmosensitivity of The Q/R site is located at the of the Tmem63b channel A and A at this site the permeability of cation Ca2+ A in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA2 and kainate receptors GluK1 and the Q/R editing occurs at the of the channel and the Ca2+ permeability (4Köhler M. Burnashev N. Sakmann B. Seeburg P.H. Determinants of Ca2+ permeability in both TM1 and TM2 of high affinity kainate receptor channels: diversity by RNA editing.Neuron. 1993; 10 (7681676): 491-50010.1016/0896-6273(93)90336-PAbstract Full Text PDF PubMed Scopus (348) Google Scholar, N. H. Seeburg P.H. Sakmann B. ion permeability of receptor is by the of a Full Text PDF PubMed Scopus Google Scholar). The splicing site is located in A and The that the in may and channel S. K. A. of the ion channel PubMed Scopus Google Scholar, J. of the channel PubMed Scopus Google Scholar). that the are to changes The of exon 4 may with the in to the of the channel regulate osmosensitivity is that the Ca2+ is by the Ca2+ permeability of the Q/R site with the of splicing the osmosensitivity by Ca2+ is are required to physiological functions of Tmem63b isoforms in the brain. were by the and of of and in with of were in of and of at with and The with site was the in at The mice were with mice by with mice C. P. K. R. R. 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In were of mice at and at a of in The were cultured in containing and primary cultured were with Tmem63b and the was with containing and were analysis and of mRNA isoforms of Tmem63b in tissues, RNA were by and and cultured with Tmem63b the were by at to the and the were by the The controls of were to the of in RNA the RNA were of Tmem63b isoforms were by system with exon and exon and exon and and and of Q/R editing in tissues, the the editing site were by and The the Q/R site were by and In the study of A-to-I editing and in the of Tmem63b were by and The sequence of was by and In the to study the coupling between alternative splicing of exon 4 and Q/R editing at exon 20 in brain the and were to the Tmem63b, the Tmem63b were by and In the to the regulation of splicing to editing in the of Tmem63b were by and the study of in the a of and and the study of in the a of The in were in Tmem63b, the were with at and by the were with at and by The were by The of was by of The efficiency of editing was by the of of to In analysis of the site is the are Q/R the editing of these were by the of A of with and were to the sequence the splicing Tmem63b with exon 4 were and by The and isoforms were by and by The were by The of was by of The were to The efficiency of exon 4 alternative splicing was by the of of to The was by H. 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