SREBP-1, A MEMBRANE-BOUND TRANSCRIPTION FACTOR RELEASED BY STEROL-REGULATED PROTEOLYSIS

Sterol regulatory element-binding protein 1 (SREBP-1), a member of the basic-helix-loop-helix-leucine zipper (bHLH-ZIP) family of transcript ion factors, is synthesized as a 125 kd precursor that is attached to the nuclear envelope and endoplasmic reticulum. In sterol-depleted cel ls, the membrane-bound precursor is cleaved to generate a soluble NH2- terminal fragment (apparent molecular mass, 68 kd) that translocates t o the nucleus. This fragment, which includes the bHLH-ZIP domain, acti vates transcription of the genes for the LDL receptor and HMG coA synt hase. Sterols inhibit the cleavage of SREBP-1, and the 68 kd nuclear f orm is rapidly catabolized, thereby reducing transcription. ALLN, an i nhibitor of neutral cysteine proteases, blocks the breakdown of the 68 kd form and superinduces sterol-regulated genes. Sterol-regulated pro teolysis of a membrane-bound transcription factor provides a novel mec hanism by which transcription can be regulated by membrane lipids.