Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved.
A central question in Hedgehog (Hh) signaling is how evolutionarily conserved components of the pathway might use the primary cilium in mammals but not fly. We focus on Suppressor of fused (Sufu), a major Hh regulator in mammals, and reveal that Sufu controls protein levels of full-length Gli transcription factors, thus affecting the production of Gli activators and repressors essential for graded Hh responses. Surprisingly, despite ciliary localization of most Hh pathway components, regulation of Gli protein levels by Sufu is cilium-independent. We propose that Sufu-dependent processes in Hh signaling are evolutionarily conserved. Consistent with this, Sufu regulates Gli protein levels by antagonizing the activity of Spop, a conserved Gli-degrading factor. Furthermore, addition of zebrafish or fly Sufu restores Gli protein function in Sufu-deficient mammalian cells. In contrast, fly Smo is unable to translocate to the primary cilium and activate the mammalian Hh pathway. We also uncover a novel positive role of Sufu in regulating Hh signaling, resulting from its control of both Gli activator and repressor function. Taken together, these studies delineate important aspects of cilium-dependent and cilium-independent Hh signal transduction and provide significant mechanistic insight into Hh signaling in diverse species.
Chen
Miao-Hsueh
MH
Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California 94158, USA.
Wilson
Christopher W
CW
Li
Ya-Jun
YJ
Law
Kelvin King Lo
KK
Lu
Chi-Sheng
CS
Gacayan
Rhodora
R
Zhang
Xiaoyun
X
Hui
Chi-chung
CC
Chuang
Pao-Tien
PT
D000818:Animals; D060466:Axin Protein; D002461:Cell Line, Transformed; D002923:Cilia / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D019143:Evolution, Molecular; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D000072079:Patched Receptors; D011956:Receptors, Cell Surface / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D043743:Ubiquitin-Protein Ligase Complexes; D015854:Up-Regulation; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
D060466:Axin Protein; D029721:Drosophila Proteins; C000618551:Gli2 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; C097059:Su(fu) protein, Drosophila; C490763:Sufu protein, mouse; C518960:Sufu protein, zebrafish; D029961:Zebrafish Proteins; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; C100664:smo protein, Drosophila; C509762:Spop protein, mouse; D043743:Ubiquitin-Protein Ligase Complexes
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