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
Affiliations
Roi Isaac
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
Yaron Vinik
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Martin Mikl
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Biology, University of Haifa, Haifa, Israel
Shani Nadav-Eliyahu
The Mina & Everard Goodman Faculty of Life Sciences and the Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 5290002, Israel
Hadas Shatz-Azoulay
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Adi Yaakobi
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Natalie DeForest
Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093, USA
Amit R. Majithia
Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
Nicholas J.G. Webster
Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; VA San Diego Healthcare System, San Diego, CA, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
Yaron Shav-Tal
The Mina & Everard Goodman Faculty of Life Sciences and the Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 5290002, Israel
Eytan Elhanany
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Yehiel Zick
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel; Corresponding author
Summary: 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.
