Based on homology with other substrates of regulated intramembrane cleavage, cleavage by regulate intramembrane proteolysis is believed to release the N-terminal cytoplasmic domain of CREB3 into the cytosol (Raggo et al. 2002, Eleveld-Trancikova et al. 2010). The fragment is then translocated into the nucleus (Raggo et al. 2002, Eleveld-Trancikova et al. 2010) where, in combination with HCF-1, it activates target genes that contain UPRE and ERSE-II elements in their promoters (Liang et al. 2006).