Tm7sf3, or transmembrane 7 superfamily member 3, is a nuclear seven-transmembrane protein with multiple important functions. It is a p53-regulated homeostatic factor that can attenuate cellular stress and the unfolded protein response [3]. It localizes to nuclear speckles and is involved in regulating alternative splicing of numerous genes, mainly at the 3' end of introns by modulating splicing factors like HNRNPK [2].

Deletion of Tm7sf3 in liver organoids, primary human hepatic stellate cells (HSCs), and in vivo in metabolic-dysfunction-associated steatohepatitis (MASH) mice accelerates HSC activation, leading to the activation of the fibrogenic program and HSC proliferation. This occurs because Tm7sf3 knockdown promotes alternative splicing of the Hippo pathway transcription factor TEAD1 by inhibiting the splicing factor hnRNPU, generating a more active form of TEAD1 and triggering HSC activation [1].

In conclusion, Tm7sf3 is crucial for maintaining cellular homeostasis and regulating alternative splicing. Its deletion in MASH mouse models reveals its key role in preventing HSC activation and the progression of MASH-related fibrosis, highlighting its potential as a therapeutic target for liver fibrosis.

References:

1. Isaac, Roi, Bandyopadhyay, Gautam, Rohm, Theresa V, Webster, Nicholas J G, Olefsky, Jerrold M. 2024. TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis. In Cell metabolism, 36, 1030-1043.e7. doi:10.1016/j.cmet.2024.04.003. https://pubmed.ncbi.nlm.nih.gov/38670107/

2. Isaac, Roi, Vinik, Yaron, Mikl, Martin, Elhanany, Eytan, Zick, Yehiel. 2022. A seven-transmembrane protein-TM7SF3, resides in nuclear speckles and regulates alternative splicing. In iScience, 25, 105270. doi:10.1016/j.isci.2022.105270. https://pubmed.ncbi.nlm.nih.gov/36304109/

3. Isaac, Roi, Goldstein, Ido, Furth, Noa, Oren, Moshe, Zick, Yehiel. 2016. TM7SF3, a novel p53-regulated homeostatic factor, attenuates cellular stress and the subsequent induction of the unfolded protein response. In Cell death and differentiation, 24, 132-143. doi:10.1038/cdd.2016.108. https://pubmed.ncbi.nlm.nih.gov/27740623/