Volume 24, No 5, May 2014

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 24 Issue 5, May 2014: 595-609

ORIGINAL ARTICLES

Hedgehog signaling downregulates Suppressor of Fused through the HIB/SPOP-Crn axis in Drosophila

Chen Liu¹, Zizhang Zhou¹, Xia Yao¹, Ping Chen¹, Man Sun¹, Miya Su¹, Cunjie Chang¹, Jun Yan¹, Jin Jiang² and Qing Zhang^1,3

¹MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Rd, Pukou District, Nanjing, Jiangsu 210061, China
²Department of Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
³Zhejiang Provincial Key Lab for Technology and Application of Model Organism, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China Correspondence: Jin Jiang, Tel: +01-2146455914 E-mail: jin.jiang@utsouthwestern.edu; Qing Zhang, Tel: +86-25-58641597(zhangqing@nju.edu.cn)

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.

10.1038/cr.2014.29

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