title: Hedgehog signaling downregulates suppressor of fused through the HIB/SPOP-Crn axis in Drosophila.
abstract: Hedgehog (Hh) signaling plays vital roles in animal development and tissue homeostasis, and its misregulation causes congenital diseases and several types of cancer. Suppressor of Fused (Su(fu)) is a conserved inhibitory component of the Hh signaling pathway, but how it is regulated remains poorly understood. Here we demonstrate that in Drosophila Hh signaling promotes downregulation of Su(fu) through its target protein HIB (Hh-induced BTB protein). Interestingly, although HIB-mediated downregulation of Su(fu) depends on the E3 ubiquitin ligase Cul3, HIB does not directly regulate Su(fu) protein stability. Through an RNAi-based candidate gene screen, we identify the spliceosome factor Crooked neck (Crn) as a regulator of Su(fu) level. Epistasis analysis indicates that HIB downregulates Su(fu) through Crn. Furthermore, we provide evidence that HIB retains Crn in the nucleus, leading to reduced Su(fu) protein level. Finally, we show that SPOP, the mammalian homologue of HIB, can substitute HIB to downregulate Su(fu) level in Drosophila. Our study suggests that Hh regulates both Ci and Su(fu) levels through its target HIB, thus uncovering a novel feedback mechanism that regulates Hh signal transduction. The dual function of HIB may provide a buffering mechanism to fine-tune Hh pathway activity.
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Rd, Pukou District, Nanjing, Jiangsu 210061, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Rd, Pukou District, Nanjing, Jiangsu 210061, China.
authors.forename: Zizhang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Rd, Pukou District, Nanjing, Jiangsu 210061, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Yao
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Rd, Pukou District, Nanjing, Jiangsu 210061, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Rd, Pukou District, Nanjing, Jiangsu 210061, China.
authors.forename: Man
authors.initials: M
authors.lastname: Sun
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Rd, Pukou District, Nanjing, Jiangsu 210061, China.
authors.forename: Miya
authors.initials: M
authors.lastname: Su
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Rd, Pukou District, Nanjing, Jiangsu 210061, China.
authors.forename: Cunjie
authors.initials: C
authors.lastname: Chang
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Rd, Pukou District, Nanjing, Jiangsu 210061, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Jiang
authors.affiliation: 1] MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Rd, Pukou District, Nanjing, Jiangsu 210061, China [2] Zhejiang Provincial Key Lab for Technology and Application of Model Organism, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D044842:Cullin Proteins / Q000378:metabolism; D015536:Down-Regulation; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C503647:Cul3 protein, Drosophila; D044842:Cullin Proteins; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C511791:Rdx protein, Drosophila; D012097:Repressor Proteins; C097059:Su(fu) protein, Drosophila; C069204:crn protein, Drosophila