Regulation of Smoothened Trafficking and Hedgehog Signaling by the SUMO Pathway

Dev Cell. 2016 Nov 21;39(4):438-451. doi: 10.1016/j.devcel.2016.09.014. Epub 2016 Oct 13.


Hedgehog (Hh) signaling plays a central role in development and diseases. Hh activates its signal transducer and GPCR-family protein Smoothened (Smo) by inducing Smo phosphorylation, but whether Smo is activated through other post-translational modifications remains unexplored. Here we show that sumoylation acts in parallel with phosphorylation to promote Smo cell-surface expression and Hh signaling. We find that Hh stimulates Smo sumoylation by dissociating it from a desumoylation enzyme Ulp1. Sumoylation of Smo in turn recruits a deubiquitinase UBPY/USP8 to antagonize Smo ubiquitination and degradation, leading to its cell-surface accumulation and elevated Hh pathway activity. We also provide evidence that Shh stimulates sumoylation of mammalian Smo (mSmo) and that sumoylation promotes ciliary localization of mSmo and Shh pathway activity. Our findings reveal a conserved mechanism whereby the SUMO pathway promotes Hh signaling by regulating Smo subcellular localization and shed light on how sumoylation regulates membrane protein trafficking.

Keywords: GPCR; Gli; PKA; SUMO; Shh; Smo; USP8; Ulp1; hedgehog; primary cilium.

MeSH terms

  • Animals
  • Cilia / metabolism
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / metabolism
  • Gene Expression Regulation
  • Hedgehog Proteins / metabolism*
  • Lysine / metabolism
  • Mammals / metabolism
  • Phosphorylation
  • Signal Transduction*
  • Small Ubiquitin-Related Modifier Proteins / metabolism*
  • Smoothened Receptor / metabolism*
  • Sumoylation
  • Ubiquitination
  • Wings, Animal / metabolism


  • Drosophila Proteins
  • Hedgehog Proteins
  • Small Ubiquitin-Related Modifier Proteins
  • Smoothened Receptor
  • smo protein, Drosophila
  • Lysine