A seven-transmembrane protein-TM7SF3, resides in nuclear speckles and regulates alternative splicing

Roi Isaac; Yaron Vinik; Martin Mikl; Shani Nadav-Eliyahu; Hadas Shatz-Azoulay; Adi Yaakobi; Natalie DeForest; Amit R. Majithia; Nicholas J.G. Webster; Yaron Shav-Tal; Eytan Elhanany; Yehiel Zick

doi:10.2139/ssrn.3732368

A seven-transmembrane protein-TM7SF3, resides in nuclear speckles and regulates alternative splicing

Roi Isaac, Yaron Vinik, Martin Mikl, Shani Nadav-Eliyahu, Hadas Shatz-Azoulay, Adi Yaakobi, Natalie DeForest, Amit R. Majithia, Nicholas J.G. Webster, Yaron Shav-Tal, Eytan Elhanany, Yehiel Zick

Department of Human Biology

Research output: Contribution to journal › Article › peer-review

Abstract

The seven-transmembrane superfamily member 3 protein (TM7SF3) is a p53-regulated homeostatic factor that attenuates cellular stress and the unfolded protein response. Here we show that TM7SF3 localizes to nuclear speckles; eukaryotic nuclear bodies enriched in splicing factors. This unexpected location for a trans-membranal protein enables formation of stable complexes between TM7SF3 and pre-mRNA splicing factors including DHX15, LARP7, HNRNPU, RBM14, and HNRNPK. Indeed, TM7SF3 regulates alternative splicing of >330 genes, mainly at the 3′end of introns by directly modulating the activity of splicing factors such as HNRNPK. These effects are observed both in cell lines and primary human pancreatic islets. Accordingly, silencing of TM7SF3 results in differential expression of 1465 genes (about 7% of the human genome); with 844 and 621 genes being up- or down-regulated, respectively. Our findings implicate TM7SF3, as a resident protein of nuclear speckles and suggest a role for seven-transmembrane proteins as regulators of alternative splicing.

Original language	English
Article number	105270
Pages (from-to)	105270
Journal	iScience
Volume	25
Issue number	11
DOIs	https://doi.org/10.2139/ssrn.3732368 https://doi.org/10.1016/j.isci.2022.105270
State	Published - 18 Nov 2022

Bibliographical note

Funding Information:
Isolated human islets (∼90% purity) were provided by the European Consortium for Islets Transplantation (Islet for Basic Research program) through a Juvenile Diabetes Research Foundation Award 31-2008-413. Islets were cultured at 37°C in a 5% CO 2 humidified atmosphere in CMRL 1066 medium containing 10% (v/v) FBS, 2mM L-glutamine, 100 units/ml penicillin, 100 μg/mL streptomycin, 0.25 μg/mL amphotericin, and 40 μg/mL gentamycin. The medium was changed every other day. Human islets studies received the WIS Ethics Committee approval. Intact human islets were dispersed by a 4 min incubation at 37°C with 1 mg/ml Trypsin/EDTA and by passing the cells twice through a 21G needle. Trypsinized islets were washed with CMRL 1066 medium containing 10% FBS and were resuspended in CMRL 1066 containing 10% FBS.

Funding Information:
Insightful discussions with Dr. Sanford Sampson (Bar Ilan University, Ramat Gan, Israel) are greatly acknowledged. YZ was supported by The Israel Science Foundation ( 776/13 ) and by the Samuil and Petr Polsky Prostate Cancer Research Fund ( 7218400101 ). ARM is supported by a UCSD /UCLA Diabetes Center Grant ( P30 DK063491 ) and by the NIH /NIDDK ( 1R01DK123422-01 ). N.D. was supported in part by a Ruth L. Kirschstein Institutional National Research Service Award T32 GM008666 from the National Institute of General Medical Sciences .

Publisher Copyright:
© 2022 The Authors

Keywords

Biochemistry
Biological sciences
Structural biology

ASJC Scopus subject areas

General

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Isaac, R., Vinik, Y., Mikl, M., Nadav-Eliyahu, S., Shatz-Azoulay, H., Yaakobi, A., DeForest, N., Majithia, A. R., Webster, N. J. G., Shav-Tal, Y., Elhanany, E., & Zick, Y. (2022). A seven-transmembrane protein-TM7SF3, resides in nuclear speckles and regulates alternative splicing. iScience, 25(11), 105270. Article 105270. https://doi.org/10.2139/ssrn.3732368, https://doi.org/10.1016/j.isci.2022.105270

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title = "A seven-transmembrane protein-TM7SF3, resides in nuclear speckles and regulates alternative splicing",

abstract = "The seven-transmembrane superfamily member 3 protein (TM7SF3) is a p53-regulated homeostatic factor that attenuates cellular stress and the unfolded protein response. Here we show that TM7SF3 localizes to nuclear speckles; eukaryotic nuclear bodies enriched in splicing factors. This unexpected location for a trans-membranal protein enables formation of stable complexes between TM7SF3 and pre-mRNA splicing factors including DHX15, LARP7, HNRNPU, RBM14, and HNRNPK. Indeed, TM7SF3 regulates alternative splicing of >330 genes, mainly at the 3′end of introns by directly modulating the activity of splicing factors such as HNRNPK. These effects are observed both in cell lines and primary human pancreatic islets. Accordingly, silencing of TM7SF3 results in differential expression of 1465 genes (about 7% of the human genome); with 844 and 621 genes being up- or down-regulated, respectively. Our findings implicate TM7SF3, as a resident protein of nuclear speckles and suggest a role for seven-transmembrane proteins as regulators of alternative splicing.",

keywords = "Biochemistry, Biological sciences, Structural biology",

author = "Roi Isaac and Yaron Vinik and Martin Mikl and Shani Nadav-Eliyahu and Hadas Shatz-Azoulay and Adi Yaakobi and Natalie DeForest and Majithia, {Amit R.} and Webster, {Nicholas J.G.} and Yaron Shav-Tal and Eytan Elhanany and Yehiel Zick",

note = "Funding Information: Isolated human islets (∼90% purity) were provided by the European Consortium for Islets Transplantation (Islet for Basic Research program) through a Juvenile Diabetes Research Foundation Award 31-2008-413. Islets were cultured at 37°C in a 5% CO 2 humidified atmosphere in CMRL 1066 medium containing 10% (v/v) FBS, 2mM L-glutamine, 100 units/ml penicillin, 100 μg/mL streptomycin, 0.25 μg/mL amphotericin, and 40 μg/mL gentamycin. The medium was changed every other day. Human islets studies received the WIS Ethics Committee approval. Intact human islets were dispersed by a 4 min incubation at 37°C with 1 mg/ml Trypsin/EDTA and by passing the cells twice through a 21G needle. Trypsinized islets were washed with CMRL 1066 medium containing 10% FBS and were resuspended in CMRL 1066 containing 10% FBS. Funding Information: Insightful discussions with Dr. Sanford Sampson (Bar Ilan University, Ramat Gan, Israel) are greatly acknowledged. YZ was supported by The Israel Science Foundation ( 776/13 ) and by the Samuil and Petr Polsky Prostate Cancer Research Fund ( 7218400101 ). ARM is supported by a UCSD /UCLA Diabetes Center Grant ( P30 DK063491 ) and by the NIH /NIDDK ( 1R01DK123422-01 ). N.D. was supported in part by a Ruth L. Kirschstein Institutional National Research Service Award T32 GM008666 from the National Institute of General Medical Sciences . Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = nov,

day = "18",

doi = "10.2139/ssrn.3732368",

language = "English",

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Isaac, R, Vinik, Y, Mikl, M, Nadav-Eliyahu, S, Shatz-Azoulay, H, Yaakobi, A, DeForest, N, Majithia, AR, Webster, NJG, Shav-Tal, Y, Elhanany, E & Zick, Y 2022, 'A seven-transmembrane protein-TM7SF3, resides in nuclear speckles and regulates alternative splicing', iScience, vol. 25, no. 11, 105270, pp. 105270. https://doi.org/10.2139/ssrn.3732368, https://doi.org/10.1016/j.isci.2022.105270

TY - JOUR

T1 - A seven-transmembrane protein-TM7SF3, resides in nuclear speckles and regulates alternative splicing

AU - Isaac, Roi

AU - Vinik, Yaron

AU - Mikl, Martin

AU - Nadav-Eliyahu, Shani

AU - Shatz-Azoulay, Hadas

AU - Yaakobi, Adi

AU - DeForest, Natalie

AU - Majithia, Amit R.

AU - Webster, Nicholas J.G.

AU - Shav-Tal, Yaron

AU - Elhanany, Eytan

AU - Zick, Yehiel

N1 - Funding Information: Isolated human islets (∼90% purity) were provided by the European Consortium for Islets Transplantation (Islet for Basic Research program) through a Juvenile Diabetes Research Foundation Award 31-2008-413. Islets were cultured at 37°C in a 5% CO 2 humidified atmosphere in CMRL 1066 medium containing 10% (v/v) FBS, 2mM L-glutamine, 100 units/ml penicillin, 100 μg/mL streptomycin, 0.25 μg/mL amphotericin, and 40 μg/mL gentamycin. The medium was changed every other day. Human islets studies received the WIS Ethics Committee approval. Intact human islets were dispersed by a 4 min incubation at 37°C with 1 mg/ml Trypsin/EDTA and by passing the cells twice through a 21G needle. Trypsinized islets were washed with CMRL 1066 medium containing 10% FBS and were resuspended in CMRL 1066 containing 10% FBS. Funding Information: Insightful discussions with Dr. Sanford Sampson (Bar Ilan University, Ramat Gan, Israel) are greatly acknowledged. YZ was supported by The Israel Science Foundation ( 776/13 ) and by the Samuil and Petr Polsky Prostate Cancer Research Fund ( 7218400101 ). ARM is supported by a UCSD /UCLA Diabetes Center Grant ( P30 DK063491 ) and by the NIH /NIDDK ( 1R01DK123422-01 ). N.D. was supported in part by a Ruth L. Kirschstein Institutional National Research Service Award T32 GM008666 from the National Institute of General Medical Sciences . Publisher Copyright: © 2022 The Authors

PY - 2022/11/18

Y1 - 2022/11/18

N2 - The seven-transmembrane superfamily member 3 protein (TM7SF3) is a p53-regulated homeostatic factor that attenuates cellular stress and the unfolded protein response. Here we show that TM7SF3 localizes to nuclear speckles; eukaryotic nuclear bodies enriched in splicing factors. This unexpected location for a trans-membranal protein enables formation of stable complexes between TM7SF3 and pre-mRNA splicing factors including DHX15, LARP7, HNRNPU, RBM14, and HNRNPK. Indeed, TM7SF3 regulates alternative splicing of >330 genes, mainly at the 3′end of introns by directly modulating the activity of splicing factors such as HNRNPK. These effects are observed both in cell lines and primary human pancreatic islets. Accordingly, silencing of TM7SF3 results in differential expression of 1465 genes (about 7% of the human genome); with 844 and 621 genes being up- or down-regulated, respectively. Our findings implicate TM7SF3, as a resident protein of nuclear speckles and suggest a role for seven-transmembrane proteins as regulators of alternative splicing.

AB - The seven-transmembrane superfamily member 3 protein (TM7SF3) is a p53-regulated homeostatic factor that attenuates cellular stress and the unfolded protein response. Here we show that TM7SF3 localizes to nuclear speckles; eukaryotic nuclear bodies enriched in splicing factors. This unexpected location for a trans-membranal protein enables formation of stable complexes between TM7SF3 and pre-mRNA splicing factors including DHX15, LARP7, HNRNPU, RBM14, and HNRNPK. Indeed, TM7SF3 regulates alternative splicing of >330 genes, mainly at the 3′end of introns by directly modulating the activity of splicing factors such as HNRNPK. These effects are observed both in cell lines and primary human pancreatic islets. Accordingly, silencing of TM7SF3 results in differential expression of 1465 genes (about 7% of the human genome); with 844 and 621 genes being up- or down-regulated, respectively. Our findings implicate TM7SF3, as a resident protein of nuclear speckles and suggest a role for seven-transmembrane proteins as regulators of alternative splicing.

KW - Biochemistry

KW - Biological sciences

KW - Structural biology

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U2 - 10.2139/ssrn.3732368

DO - 10.2139/ssrn.3732368

M3 - Article

C2 - 36304109

AN - SCOPUS:85140388861

SN - 2589-0042

VL - 25

SP - 105270

JO - iScience

JF - iScience

IS - 11

M1 - 105270

ER -

A seven-transmembrane protein-TM7SF3, resides in nuclear speckles and regulates alternative splicing

Abstract

Bibliographical note

Keywords

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