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Published online on April 11, 2007, 10.1073/pnas.0700899104
PNAS | April 17, 2007 | vol. 104 | no. 16 | 6511-6518
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From the Cover
FEATURE ARTICLE / BIOLOGICAL SCIENCES / BIOCHEMISTRY
Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Oxysterols block transport by binding to Insig

Arun Radhakrishnan*, Yukio Ikeda*, Hyock Joo Kwon{dagger}, Michael S. Brown*,{ddagger}, and Joseph L. Goldstein*,{ddagger}

Departments of *Molecular Genetics and {dagger}Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390

Edited by Randy Schekman, University of California, Berkeley, CA, and approved February 20, 2007 (received for review January 31, 2007)

Cholesterol synthesis in animals is controlled by the regulated transport of sterol regulatory element-binding proteins (SREBPs) from the endoplasmic reticulum to the Golgi, where the transcription factors are processed proteolytically to release active fragments. Transport is inhibited by either cholesterol or oxysterols, blocking cholesterol synthesis. Cholesterol acts by binding to the SREBP-escort protein Scap, thereby causing Scap to bind to anchor proteins called Insigs. Here, we show that oxysterols act by binding to Insigs, causing Insigs to bind to Scap. Mutational analysis of the six transmembrane helices of Insigs reveals that the third and fourth are important for Insig's binding to oxysterols and to Scap. These studies define Insigs as oxysterol-binding proteins, explaining the long-known ability of oxysterols to inhibit cholesterol synthesis in animal cells.

cholesterol homeostasis | Scap | sterol regulatory element-binding protein pathway | COPII vesicles

Freely available online through the PNAS open access option.

Author contributions: A.R., Y.I., H.J.K., M.S.B., and J.L.G. designed research; A.R. and Y.I. performed research; A.R., Y.I., H.J.K., M.S.B., and J.L.G. analyzed data; and A.R., M.S.B., and J.L.G. wrote the paper.

This Feature Article is part of a series identified by the Editorial Board as reporting findings of exceptional significance.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

See Commentary on page 6496.

This article contains supporting information online at www.pnas.org/cgi/content/full/0700899104/DC1.

{ddagger}To whom correspondence may be addressed. E-mail: mike.brown{at}utsouthwestern.edu or joe.goldstein{at}utsouthwestern.edu

© 2007 by The National Academy of Sciences of the USA


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