Identification of a degradation signal at the carboxy terminus of SREBP2: A new role for this domain in cholesterol homeostasis

Daniel L. Kober, Shimeng Xu, Shili Li, Bilkish Bajaj, Guosheng Liang, Daniel M. Rosenbaum, Arun Radhakrishnan

Research output: Contribution to journalArticlepeer-review

Abstract

Lipid homeostasis in animal cells is maintained by sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors whose proteolytic activation requires the cholesterol-sensing membrane protein Scap. In endoplasmic reticulum (ER) membranes, the carboxyl-terminal domain (CTD) of SREBPs binds to the CTD of Scap. When cholesterol levels are low, Scap escorts SREBPs from the ER to the Golgi, where the actions of two proteases release the amino-terminal domains of SREBPs that travel to the nucleus to up-regulate expression of lipogenic genes. The CTD of SREBP remains bound to Scap but must be eliminated so that Scap can be recycled to bind and transport additional SREBPs. Here, we provide insights into how this occurs by performing a detailed molecular dissection of the CTD of SREBP2, one of three SREBP isoforms expressed in mammals. We identify a degradation signal comprised of seven noncontiguous amino acids encoded in exon 19 that mediates SREBP2’s proteasomal degradation in the absence of Scap. When bound to the CTD of Scap, this signal is masked and SREBP2 is stabilized. Binding to Scap requires an arginine residue in exon 18 of SREBP2. After SREBP2 is cleaved in Golgi, its CTD remains bound to Scap and returns to the ER with Scap where it is eliminated by proteasomal degradation. The Scap-binding motif, but not the degradation signal, is conserved in SREBP1. SREBP1’s stability is determined by a degradation signal in a different region of its CTD. These findings highlight a previously unknown role for the CTD of SREBPs in regulating SREBP activity.

Original languageEnglish (US)
Pages (from-to)28080-28091
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number45
DOIs
StatePublished - Nov 10 2020

Keywords

  • Scap | cholesterol | endoplasmic reticulum | Golgi | proteasome

ASJC Scopus subject areas

  • General

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