CREB3L3 is a 461 amino acid single-pass type II membrane protein that localizes to the endoplasmic reticulum (ER) and, in response to ER stress, is cleaved and translocated to the nucleus. Expressed exclusively in liver, CREB3L3 functions as a transcription factor that, during ER stress, is thought to activate genes that are involved in both the unfolded protein response and the acute phase response (APR). Additionally, CREB3L3 is underexpressed in hepatocellular carcinoma, suggesting a possible role as a tumor suppressor. CREB3L3 functions as a dimer and contains one leucine zipper domain, a KDEL-like sequence and a bZIP domain, through which it conveys its DNA binding ability. Three isoforms of CREB3L3 exist due to alternative splicing events.