The Integrator complex desensitizes cellular response to TGF-b/BMP signaling

Maintenance of stem cells requires the concerted actions of niche-derived signals and stem cell-intrinsic fac-tors. Although Decapentaplegic (Dpp), a Drosophila bone morphogenetic protein (BMP) molecule, can act as a long-range morphogen, its function is spatially limited to the germline stem cell niche in the germarium. We show here that Integrator, a complex known to be involved in RNA polymerase II (RNAPII)-mediated tran-scriptional regulation in the nucleus, promotes germline differentiation by restricting niche-derived Dpp/ BMP activity in the cytoplasm. Further results show that Integrator works in various developmental contexts to desensitize the cellular response to Dpp/BMP signaling during Drosophila development. Mechanistically, our results show that Integrator forms a multi-subunit complex with the type I receptor Thickveins (Tkv) and other Dpp/BMP signaling components and acts in a negative feedback loop to promote Tkv turnover inde-pendent of its transcriptional activity. Similarly, human Integrator subunits bind transforming growth factor b (TGF-b)/BMP signaling components and antagonize their activity, suggesting a conserved role of Integrator across metazoans.

Automated summary

Maintenance of stem cells relies on both niche-derived signals and stem cell-intrinsic factors. Integrator, a complex involved in transcriptional regulation, is found to promote germline differentiation by restricting the activity of niche-derived Dpp/BMP in the cytoplasm. It forms a multi-subunit complex with the receptor Tkv and other signaling components to negatively regulate Tkv turnover, independent of its transcriptional activity. Similar roles of Integrator are observed in human cells, suggesting conservation across metazoans.