CREB3 Gene - Function, Mutations, and Associated Diseases

CREB3 (cAMP Responsive Element Binding Protein 3) encodes a transcription factor belonging to the basic leucine zipper (bZIP) family. It is a membrane-bound protein localized to the endoplasmic reticulum (ER) and Golgi apparatus. Under ER stress, CREB3 is cleaved by regulated intramembrane proteolysis, releasing its N-terminal domain to translocate to the nucleus and activate target genes involved in the unfolded protein response (UPR), cell differentiation, and viral latency. CREB3 also plays roles in osteoblast differentiation and cancer progression.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Unfolded Protein Response (UPR) - Reactome R-HSA-381119

• ATF6-alpha activates chaperones - Reactome R-HSA-381033

• Regulated Intramembrane Proteolysis of CREB3 - PubMed

CREB3 is a 371-amino acid transcription factor with an N-terminal bZIP domain, a transmembrane domain, and a C-terminal ER luminal region. It is synthesized as a precursor anchored in the ER membrane. Upon ER stress or specific signals, it undergoes site-1 and site-2 protease cleavage, releasing the N-terminal fragment that enters the nucleus to activate genes such as HERPUD1 and EDEM1. The protein is involved in cellular stress responses, differentiation, and viral latency. Post-translational modifications include glycosylation and phosphorylation.