A hedgehog-induced BTB protein modulates hedgehog signaling by degrading Ci/Gli transcription factor.
The Ci/Gli family of transcription factors mediates Hedgehog (Hh) signaling in many key developmental processes. Here we identify a Hh-induced MATH and BTB domain containing protein (HIB) as a negative regulator of the Hh pathway. Overexpressing HIB down regulates Ci and blocks Hh signaling, whereas inactivating HIB results in Ci accumulation and enhanced pathway activity. HIB binds the N- and C-terminal regions of Ci, both of which mediate Ci degradation. HIB forms a complex with Cul3, a scaffold for modular ubiquitin ligases, and promotes Ci ubiquitination and degradation through Cul3. Furthermore, HIB-mediated Ci degradation is stimulated by Hh and inhibited by Suppressor of Fused (Sufu). The mammalian homolog of HIB, SPOP, can functionally substitute for HIB, and Gli proteins are degraded by HIB/SPOP in Drosophila. We provide evidence that HIB prevents aberrant Hh signaling posterior to the morphogenic furrow, which is essential for normal eye development.
Zhang
Qing
Q
Center for Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
Zhang
Lei
L
Wang
Bing
B
Ou
Chan-Yen
CY
Chien
Cheng-Ting
CT
Jiang
Jin
J
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004330:Drosophila / Q000166:cytology / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004625:Embryo, Nonmammalian; D017353:Gene Deletion; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D017344:Genes, Insect; D005982:Glutathione Transferase / Q000378:metabolism; D053823:Hedgehog Proteins; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019076:Transgenes; D000071676:Zinc Finger Protein GLI1
D018797:Cell Cycle Proteins; C503647:Cul3 protein, Drosophila; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D019476:Insect Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; C511791:Rdx protein, Drosophila; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C092937:ci protein, Drosophila; D005982:Glutathione Transferase; D046988:Proteasome Endopeptidase Complex