Regulation of Smoothened Trafficking and Hedgehog Signaling by the SUMO Pathway

Guoqiang Ma, Shuang Li, Yuhong Han, Shuangxi Li, Tao Yue, Bing Wang, Jin Jiang

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)438-451
Number of pages14
JournalDevelopmental Cell
Volume39
Issue number4
DOIs
StatePublished - Nov 21 2016

Fingerprint

Sumoylation
Phosphorylation
Transducers
Membrane Proteins
Degradation
Ubiquitination
Protein Transport
Enzymes
Post Translational Protein Processing
Proteins

Keywords

  • Gli
  • GPCR
  • hedgehog
  • PKA
  • primary cilium
  • Shh
  • Smo
  • SUMO
  • Ulp1
  • USP8

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Regulation of Smoothened Trafficking and Hedgehog Signaling by the SUMO Pathway. / Ma, Guoqiang; Li, Shuang; Han, Yuhong; Li, Shuangxi; Yue, Tao; Wang, Bing; Jiang, Jin.

In: Developmental Cell, Vol. 39, No. 4, 21.11.2016, p. 438-451.

Research output: Contribution to journalArticle

Ma, Guoqiang ; Li, Shuang ; Han, Yuhong ; Li, Shuangxi ; Yue, Tao ; Wang, Bing ; Jiang, Jin. / Regulation of Smoothened Trafficking and Hedgehog Signaling by the SUMO Pathway. In: Developmental Cell. 2016 ; Vol. 39, No. 4. pp. 438-451.
@article{ecd7d774a7a8451f8a3aba23b9d3aae2,
title = "Regulation of Smoothened Trafficking and Hedgehog Signaling by the SUMO Pathway",
abstract = "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 = "Gli, GPCR, hedgehog, PKA, primary cilium, Shh, Smo, SUMO, Ulp1, USP8",
author = "Guoqiang Ma and Shuang Li and Yuhong Han and Shuangxi Li and Tao Yue and Bing Wang and Jin Jiang",
year = "2016",
month = "11",
day = "21",
doi = "10.1016/j.devcel.2016.09.014",
language = "English (US)",
volume = "39",
pages = "438--451",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "4",

}

TY - JOUR

T1 - Regulation of Smoothened Trafficking and Hedgehog Signaling by the SUMO Pathway

AU - Ma, Guoqiang

AU - Li, Shuang

AU - Han, Yuhong

AU - Li, Shuangxi

AU - Yue, Tao

AU - Wang, Bing

AU - Jiang, Jin

PY - 2016/11/21

Y1 - 2016/11/21

N2 - 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.

AB - 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.

KW - Gli

KW - GPCR

KW - hedgehog

KW - PKA

KW - primary cilium

KW - Shh

KW - Smo

KW - SUMO

KW - Ulp1

KW - USP8

UR - http://www.scopus.com/inward/record.url?scp=84997542928&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84997542928&partnerID=8YFLogxK

U2 - 10.1016/j.devcel.2016.09.014

DO - 10.1016/j.devcel.2016.09.014

M3 - Article

C2 - 27746045

AN - SCOPUS:84997542928

VL - 39

SP - 438

EP - 451

JO - Developmental Cell

JF - Developmental Cell

SN - 1534-5807

IS - 4

ER -