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

  • Cell Rep. 2023 Jan 31;42(1):112007. doi: 10.1016/j.celrep.2023.112007.
Sen Liu  1 ,  Gyeong Hun Baeg  2 ,  Ying Yang  1 ,  Feng Guang Goh  3 ,  Hongcun Bao  4 ,  Eric J Wagner  5 ,  Xiaohang Yang  4 ,  Yu Cai  6
Affiliations
  • 1. Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore 117604, Singapore.
  • 2. Faculty of Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau SAR, China.
  • 3. Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore 117604, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
  • 4. The Women's Hospital and Institute of Genetics, School of Medicine, Zhejiang University, Hang Zhou 310058, China.
  • 5. Department of Biochemistry and Biophysics, Center for RNA Biology, Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, KMRB B.9629, Rochester, NY 14642 USA.
  • 6. Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore 117604, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore. Electronic address: [email protected].
PMID: 36641752 DOI: 10.1016/j.celrep.2023.112007
Abstract

Maintenance of stem cells requires the concerted actions of niche-derived signals and stem cell-intrinsic factors. 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 transcriptional 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 independent of its transcriptional activity. Similarly, human Integrator subunits bind transforming growth factor β (TGF-β)/BMP signaling components and antagonize their activity, suggesting a conserved role of Integrator across metazoans.

Keywords
CP: Cell biology; CP: Stem cell research; Dpp/BMP signaling; Drosophila; E3 ubiquitin ligase; I-Smad; Integrator; Smurf; TGF-β/BMP signaling; germline stem cells; stem cell niche; stem cells.