Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment

Juro Sakai, Elizabeth A. Duncan, Robert B. Rawson, Xianxin Hua, Michael S. Brown, Joseph L. Goldstein

Research output: Contribution to journalArticle

392 Scopus citations


Sterol regulatory element binding proteins (SREBPs) are transcription factors attached to the endoplasmic reticulum. The NH2-segment, which activates transcription, is connected to membranes by a hairpin anchor formed by two transmembrane sequences and a short lumenal loop. Using H-Ras-SREBP-2 fusion proteins, we show that the NH2-segment is released from membranes by two sequential cleavages. The first, regulated by sterols, occurs in the lumenal loop. The second, not regulated by sterols, occurs within the first transmembrane domain. The liberated NH2-segment enters the nucleus and activates genes controlling cholesterol synthesis and uptake. Certain mutant Chinese hamster ovary cells are auxotrophic for cholesterol because they fail to carry out the second cleavage; the NH2-segment remains membrane-bound and transcription is not activated.

Original languageEnglish (US)
Pages (from-to)1037-1046
Number of pages10
Issue number7
StatePublished - Jun 28 1996


ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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