title: Suppressor of fused impedes Ci/Gli nuclear import by opposing Trn/Kapβ2 in Hedgehog signaling.
abstract: The Hedgehog (Hh) family of secreted proteins governs many key developmental processes by regulating Ci/Gli transcription factors at multiple levels including nuclear-cytoplasmic shuttling. Here, we investigate the mechanism underlying the regulation of Ci/Gli subcellular localization by identifying and characterizing a novel nuclear localization sequence (NLS) in the N-terminal conserved domain of Ci/Gli that matches the PY-NLS consensus. We demonstrate that the PY-NLS functions in parallel with a previously identified bipartite NLS to promote nuclear localization and activity of full-length Ci. We find that Transportin (Trn), the Drosophila homolog of Kapβ2, is responsible for PY-NLS-mediated nuclear localization of Ci. Furthermore, we show that the tumor suppressor and conserved Hh pathway component Suppressor of fused (Sufu) opposes Trn-mediated Ci nuclear import by masking its PY-NLS. Finally, we provide evidence that Gli proteins also contain a functional PY-NLS and that mammal Sufu uses a similar mechanism to regulate nuclear translocation of Gli. Our study not only provides a mechanistic insight into how Sufu regulates Hh signaling and the subcellular localization of Ci/Gli, but also reveals a role for Trn/Kapβ2 in developmental regulation.
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9133, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Han
authors.forename: Jin
authors.initials: J
authors.lastname: Jiang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D004331:Drosophila melanogaster / Q000378:metabolism*; D028884:Karyopherins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D015513:Oncogene Proteins / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D028884:Karyopherins; D008565:Membrane Proteins; D019913:Nuclear Localization Signals; D015513:Oncogene Proteins; D012097:Repressor Proteins; C097059:Su(fu) protein, Drosophila; C000592699:Tnpo protein, Drosophila; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C092937:ci protein, Drosophila; C084647:trn protein, Drosophila
keywords: Ci; Gli; Hedgehog; PY-NLS; Sufu; Transportin