Cholesterol accessibility at the ciliary membrane controls hedgehog signaling

被引:96
|
作者
Kinnebrew, Maia [1 ]
Iverson, Ellen J. [1 ]
Patel, Bhaven B. [1 ]
Pusapati, Ganesh V. [1 ]
Kong, Jennifer H. [1 ]
Johnson, Kristen A. [2 ]
Luchetti, Giovanni [1 ,8 ]
Eckert, Kaitlyn M. [3 ]
McDonald, Jeffrey G. [2 ,3 ]
Covey, Douglas F. [4 ,5 ]
Siebold, Christian [6 ]
Radhakrishnan, Arun [2 ]
Rohatgi, Rajat [1 ,7 ]
机构
[1] Stanford Univ, Dept Biochem, Sch Med, Stanford, CA 94305 USA
[2] Univ Texas Southwestern Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA
[3] Univ Texas Southwestern Med Ctr Dallas, Ctr Human Nutr, Dallas, TX USA
[4] Washington Univ, Sch Med, Taylor Family Inst Innovat Psychiat Res, St Louis, MO USA
[5] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO USA
[6] Univ Oxford, Wellcome Ctr Human Genet, Div Struct Biol, Oxford, England
[7] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA
[8] Genentech Inc, Dept Physiol Chem, San Francisco, CA USA
来源
ELIFE | 2019年 / 8卷
基金
欧洲研究理事会; 美国国家卫生研究院; 美国国家科学基金会;
关键词
PLASMA-MEMBRANES; INTRAFLAGELLAR TRANSPORT; CONDENSED COMPLEXES; ACTIVATION; OXYSTEROLS; STEROL; SPHINGOMYELIN; PHOSPHOLIPIDS; TRAFFICKING; DEPLETION;
D O I
10.7554/eLife.50051
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Previously we proposed that transmission of the hedgehog signal across the plasma membrane by Smoothened is triggered by its interaction with cholesterol (Luchetti et al., 2016). But how is cholesterol, an abundant lipid, regulated tightly enough to control a signaling system that can cause birth defects and cancer? Using toxin-based sensors that distinguish between distinct pools of cholesterol, we find that Smoothened activation and Hedgehog signaling are driven by a biochemically-defined, small fraction of membrane cholesterol, termed accessible cholesterol. Increasing cholesterol accessibility by depletion of sphingomyelin, which sequesters cholesterol in complexes, amplifies Hedgehog signaling. Hedgehog ligands increase cholesterol accessibility in the membrane of the primary cilium by inactivating the transporter-like protein Patched 1. Trapping this accessible cholesterol blocks Hedgehog signal transmission across the membrane. Our work shows that the organization of cholesterol in the ciliary membrane can be modified by extracellular ligands to control the activity of cilia-localized signaling proteins.
引用
收藏
页数:28
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