Stabilization of speckle-type POZ protein (Spop) by Daz interacting protein 1 (Dzip1) is essential for Gli turnover and the proper output of Hedgehog signaling.
The Hedgehog (Hh) pathway is essential for embryonic development and adult tissue homeostasis. The Gli/Cubitus interruptus (Ci) family of transcription factors acts at the downstream end of the pathway to mediate Hh signaling. Both Hh-dependent and -independent Gli regulatory mechanisms are important for the output of Hh signaling. Daz interacting protein 1 (Dzip1) has bipartite positive and negative functions in the Hh pathway. The positive Hh regulatory function appears to be attributed to a requirement for Dzip1 during ciliogenesis. The mechanism by which Dzip1 inhibits Hh signaling, however, remains largely unclear. We recently found that Dzip1 is required for Gli turnover, which may account for its inhibitory function in Hh signaling. Here, we report that Dzip1 regulates Gli/Ci turnover by preventing degradation of speckle-type POZ protein (Spop), a protein that promotes proteasome-dependent turnover of Gli proteins. We provide evidence that Dzip1 regulates the stability of Spop independent of its function in ciliogenesis. Partial knockdown of Dzip1 to levels insufficient for perturbing ciliogenesis, sensitized Xenopus embryos to Hh signaling, leading to phenotypes that resemble activation of Hh signaling. Importantly, overexpression of Spop was able to restore proper Gli protein turnover and rescue phenotypes in Dzip1-depleted embryos. Consistently, depletion of Dzip1 in Drosophila S2 cells destabilized Hh-induced BTB protein (HIB), the Drosophila homolog of Spop, and increased the level of Ci. Thus, Dzip1-dependent stabilization of Spop/HIB is evolutionarily conserved and essential for proper regulation of Gli/Ci proteins in the Hh pathway.
From the Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802.
Tyler
T
Schwend
From the Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802.
Zhigang
Z
Jin
Markey Cancer Center, Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536-0509.
Kai
K
Jiang
Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611.
Brian J
BJ
Mitchell
Markey Cancer Center, Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536-0509.
Jianhang
J
Jia
From the Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802,. Electronic address: yangj@illinois.edu.
Jing
J
Yang
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D004625:Embryo, Nonmammalian / Q000196:embryology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis; D000071676:Zinc Finger Protein GLI1
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C492524:DZIP1 protein, human; D029721:Drosophila Proteins; C511358:Dzip1 protein, mouse; C400551:GLI1 protein, human; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; C511791:Rdx protein, Drosophila; D012097:Repressor Proteins; C509239:SHH protein, human; C509761:SPOP protein, human; C578287:Shh protein, Drosophila; C558166:Shh protein, Xenopus; C465570:Shh protein, mouse; D014157:Transcription Factors; D029867:Xenopus Proteins; D000071676:Zinc Finger Protein GLI1; C509762:Spop protein, mouse; D043743:Ubiquitin-Protein Ligase Complexes
Cilia; Development; Dzip1; Gli; Hedgehog; Protein Degradation; Spop; Xenopus