PLoS Genetics (May 2016)

Ubr3, a Novel Modulator of Hh Signaling Affects the Degradation of Costal-2 and Kif7 through Poly-ubiquitination.

  • Tongchao Li,
  • Junkai Fan,
  • Bernardo Blanco-Sánchez,
  • Nikolaos Giagtzoglou,
  • Guang Lin,
  • Shinya Yamamoto,
  • Manish Jaiswal,
  • Kuchuan Chen,
  • Jie Zhang,
  • Wei Wei,
  • Michael T Lewis,
  • Andrew K Groves,
  • Monte Westerfield,
  • Jianhang Jia,
  • Hugo J Bellen

DOI
https://doi.org/10.1371/journal.pgen.1006054
Journal volume & issue
Vol. 12, no. 5
p. e1006054

Abstract

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Hedgehog (Hh) signaling regulates multiple aspects of metazoan development and tissue homeostasis, and is constitutively active in numerous cancers. We identified Ubr3, an E3 ubiquitin ligase, as a novel, positive regulator of Hh signaling in Drosophila and vertebrates. Hh signaling regulates the Ubr3-mediated poly-ubiquitination and degradation of Cos2, a central component of Hh signaling. In developing Drosophila eye discs, loss of ubr3 leads to a delayed differentiation of photoreceptors and a reduction in Hh signaling. In zebrafish, loss of Ubr3 causes a decrease in Shh signaling in the developing eyes, somites, and sensory neurons. However, not all tissues that require Hh signaling are affected in zebrafish. Mouse UBR3 poly-ubiquitinates Kif7, the mammalian homologue of Cos2. Finally, loss of UBR3 up-regulates Kif7 protein levels and decreases Hh signaling in cultured cells. In summary, our work identifies Ubr3 as a novel, evolutionarily conserved modulator of Hh signaling that boosts Hh in some tissues.