摘要：SummaryThe 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 atrans-membranalprotein 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.Graphical abstractDisplay OmittedHighlights•TM7SF3 is the first heptahelical protein and resides mainly in nuclear speckles•TM7SF3 binds proteins involved in RNA processing and regulates alternative splicing•TM7SF3 binds splicing factors such as HNRNPK and inhibits their splicing activity•TM7SF3 knockdown affects expression of >1450 genes and promotes cellular stressBiological sciences; Biochemistry; Structural biology.
