The E3 ubiquitin ligase RNF5, an endoplasmic reticulum-anchored protein, mediates Lys29-linked polyubiquitination of SCAP, thereby activating SREBP2. RNF5 combinatorially inhibits SREBP2 activation and reduces cholesterol biosynthesis in human hepatocellular carcinoma cells. The gene discussed is SCAP; the disease is hepatocellular carcinoma.