Sterol Regulatory Element-binding Protein (SREBP) Cleavage Regulates Golgi-to-ER Recycling of SREBP Cleavage Activating Protein (SCAP) [Gene Regulation]

January 29th, 2014 by Shao, W., Espenshade, P. J.

Sterol regulatory element-binding protein (SREBP) transcription factors are central regulators of cellular lipogenesis. Release of membrane-bound SREBP requires SREBP cleavage activation protein (SCAP) to escort SREBP from the ER to 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 demonstrate 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.
  • Posted in Journal of Biological Chemistry, Publications
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