Sterol regulatory element-binding protein (SREBP) cleavage regulates Golgi-to-endoplasmic reticulum recycling of SREBP cleavage-activating protein (SCAP).
Sterol regulatory element-binding protein (SREBP) transcription factors are central regulators of cellular lipogenesis. Release of membrane-bound SREBP requires SREBP cleavage-activating protein (SCAP) to escort SREBP from the endoplasmic reticulum (ER) to the Golgi for cleavage by site-1 and site-2 proteases. SCAP then recycles to the ER for additional rounds of SREBP binding and transport. Mechanisms regulating ER-to-Golgi transport of SCAP-SREBP are understood in molecular detail, but little is known about SCAP recycling. Here, we have demonstrated that SCAP Golgi-to-ER transport requires cleavage of SREBP at site-1. Reductions in SREBP cleavage lead to SCAP degradation in lysosomes, providing additional negative feedback control to the SREBP pathway. Current models suggest that SREBP plays a passive role prior to cleavage. However, we show that SREBP actively prevents premature recycling of SCAP-SREBP until initiation of SREBP cleavage. SREBP regulates SCAP in human cells and yeast, indicating that this is an ancient regulatory mechanism.
From the Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Wei
W
Shao
Peter J
PJ
Espenshade
D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000378:metabolism; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005822:Genetic Vectors; D006056:Golgi Apparatus / Q000378:metabolism*; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D011485:Protein Binding; D012568:Schizosaccharomyces / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D008565:Membrane Proteins; C102196:SREBP cleavage-activating protein; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D002784:Cholesterol
Cholesterol; Lipids; Lysosomes; Protein Degradation; Recycling; SCAP; SREBP; Transcription Factors