Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: oxysterols block transport by binding to Insig.
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.
Radhakrishnan
Arun
A
Department of Molecular Genetics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Ikeda
Yukio
Y
Kwon
Hyock Joo
HJ
Brown
Michael S
MS
Goldstein
Joseph L
JL
D000595:Amino Acid Sequence; D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism*; D006056:Golgi Apparatus / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry / Q000378:metabolism*; D017665:Hydroxyl Radical / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D011987:Receptors, Steroid / Q000737:chemistry / Q000378:metabolism*; D051779:Sterol Regulatory Element Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D000098825:Oxysterol Binding Proteins
D000924:Anticholesteremic Agents; D006888:Hydroxycholesterols; C108626:INSIG1 protein, human; C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011987:Receptors, Steroid; C102196:SREBP cleavage-activating protein; D051779:Sterol Regulatory Element Binding Proteins; D000098825:Oxysterol Binding Proteins; D017665:Hydroxyl Radical; C007997:25-hydroxycholesterol