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:10.1016/j.isci.2022.105270

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

iScience. 2022 Oct 4;25(11):105270. doi: 10.1016/j.isci.2022.105270. eCollection 2022 Nov 18.

Authors

Roi Isaac^{1

2}, Yaron Vinik¹, Martin Mikl^{1

3}, Shani Nadav-Eliyahu⁴, Hadas Shatz-Azoulay¹, Adi Yaakobi¹, Natalie DeForest^{2

5}, Amit R Majithia^{2

6}, Nicholas J G Webster^{2

7

8}, Yaron Shav-Tal⁴, Eytan Elhanany¹, Yehiel Zick¹

Affiliations

¹ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
² Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
³ Department of Biology, University of Haifa, Haifa, Israel.
⁴ The Mina & Everard Goodman Faculty of Life Sciences and the Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 5290002, Israel.
⁵ Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093, USA.
⁶ Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
⁷ VA San Diego Healthcare System, San Diego, CA, USA.
⁸ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.

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.

Abstract

Grants and funding