Cholesterol Modification of Smoothened Is Required for Hedgehog Signaling

Xu Xiao; Jing Jie Tang; Chao Peng; Yan Wang; Lin Fu; Zhi Ping Qiu; Yue Xiong; Lian Fang Yang; Hai Wei Cui; Xiao Long He; Lei Yin; Wei Qi; Catherine C.L. Wong; Yun Zhao; Bo Liang Li; Wen Wei Qiu; Bao Liang Song

doi:10.1016/j.molcel.2017.02.015

Cholesterol Modification of Smoothened Is Required for Hedgehog Signaling

Xu Xiao
, Jing Jie Tang
, Chao Peng
, Yan Wang
, Lin Fu
, Zhi Ping Qiu
, Yue Xiong
, Lian Fang Yang
, Hai Wei Cui
, Xiao Long He
, Lei Yin
, Wei Qi
, Catherine C.L. Wong
, Yun Zhao
, Bo Liang Li
, Wen Wei Qiu^*
, Bao Liang Song

^*Corresponding author for this work

School of Chemistry and Molecular Engineering

Research output: Contribution to journal › Article › peer-review

196 Scopus citations

Abstract

Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling. Furthermore, homozygous Smo^D99N/D99N (the equivalent residue in mouse) knockin mice were embryonic lethal with severe cardiac defects, phenocopying the Smo^−/− mice. Together, the results of our study suggest that Hh signaling transduces to SMO through modulating its cholesterylation and provides a therapeutic opportunity to treat Hh-pathway-related cancers by targeting SMO cholesterylation.

Original language	English
Pages (from-to)	154-162.e10
Journal	Molecular Cell
Volume	66
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2017.02.015
State	Published - 6 Apr 2017

Keywords

Hedgehog
Patched-1
Smoothened
cholesterol
cholesterylation
ciliary localization
click chemistry
cysteine-rich domain
embryonic lethal
primary cilia

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.molcel.2017.02.015

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title = "Cholesterol Modification of Smoothened Is Required for Hedgehog Signaling",

abstract = "Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling. Furthermore, homozygous SmoD99N/D99N (the equivalent residue in mouse) knockin mice were embryonic lethal with severe cardiac defects, phenocopying the Smo−/− mice. Together, the results of our study suggest that Hh signaling transduces to SMO through modulating its cholesterylation and provides a therapeutic opportunity to treat Hh-pathway-related cancers by targeting SMO cholesterylation.",

keywords = "Hedgehog, Patched-1, Smoothened, cholesterol, cholesterylation, ciliary localization, click chemistry, cysteine-rich domain, embryonic lethal, primary cilia",

author = "Xu Xiao and Tang, \{Jing Jie\} and Chao Peng and Yan Wang and Lin Fu and Qiu, \{Zhi Ping\} and Yue Xiong and Yang, \{Lian Fang\} and Cui, \{Hai Wei\} and He, \{Xiao Long\} and Lei Yin and Wei Qi and Wong, \{Catherine C.L.\} and Yun Zhao and Li, \{Bo Liang\} and Qiu, \{Wen Wei\} and Song, \{Bao Liang\}",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

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day = "6",

doi = "10.1016/j.molcel.2017.02.015",

language = "英语",

volume = "66",

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journal = "Molecular Cell",

issn = "1097-2765",

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TY - JOUR

T1 - Cholesterol Modification of Smoothened Is Required for Hedgehog Signaling

AU - Xiao, Xu

AU - Tang, Jing Jie

AU - Peng, Chao

AU - Wang, Yan

AU - Fu, Lin

AU - Qiu, Zhi Ping

AU - Xiong, Yue

AU - Yang, Lian Fang

AU - Cui, Hai Wei

AU - He, Xiao Long

AU - Yin, Lei

AU - Qi, Wei

AU - Wong, Catherine C.L.

AU - Zhao, Yun

AU - Li, Bo Liang

AU - Qiu, Wen Wei

AU - Song, Bao Liang

PY - 2017/4/6

Y1 - 2017/4/6

N2 - Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling. Furthermore, homozygous SmoD99N/D99N (the equivalent residue in mouse) knockin mice were embryonic lethal with severe cardiac defects, phenocopying the Smo−/− mice. Together, the results of our study suggest that Hh signaling transduces to SMO through modulating its cholesterylation and provides a therapeutic opportunity to treat Hh-pathway-related cancers by targeting SMO cholesterylation.

AB - Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling. Furthermore, homozygous SmoD99N/D99N (the equivalent residue in mouse) knockin mice were embryonic lethal with severe cardiac defects, phenocopying the Smo−/− mice. Together, the results of our study suggest that Hh signaling transduces to SMO through modulating its cholesterylation and provides a therapeutic opportunity to treat Hh-pathway-related cancers by targeting SMO cholesterylation.

KW - Hedgehog

KW - Patched-1

KW - Smoothened

KW - cholesterol

KW - cholesterylation

KW - ciliary localization

KW - click chemistry

KW - cysteine-rich domain

KW - embryonic lethal

KW - primary cilia

UR - https://www.scopus.com/pages/publications/85016062049

U2 - 10.1016/j.molcel.2017.02.015

DO - 10.1016/j.molcel.2017.02.015

M3 - 文章

C2 - 28344083

AN - SCOPUS:85016062049

SN - 1097-2765

VL - 66

SP - 154-162.e10

JO - Molecular Cell

JF - Molecular Cell

IS - 1

ER -

Cholesterol Modification of Smoothened Is Required for Hedgehog Signaling

Abstract

Keywords

UN SDGs

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