CREB3 subfamily transcription factors are not created equal: Recent insights from global analyses and animal models

Abstract

The CREB3 subfamily of membrane-bound bZIP transcription factors has five members in mammals known as CREB3 and CREB3L1-L4. One current model suggests that CREB3 subfamily transcription factors are similar to ATF6 in regulated intramembrane proteolysis and transcriptional activation. Particularly, they were all thought to be proteolytically activated in response to endoplasmic reticulum (ER) stress to stimulate genes that are involved in unfolded protein response (UPR). Although the physiological inducers of their proteolytic activation remain to be identified, recent findings from microarray analyses, RNAi screens and gene knockouts not only demonstrated their critical roles in regulating development, metabolism, secretion, survival and tumorigenesis, but also revealed cell type-specific patterns in the activation of their target genes. Members of the CREB3 subfamily show differential activity despite their structural similarity. The spectrum of their biological function expands beyond ER stress and UPR. Further analyses are required to elucidate the mechanism of their proteolytic activation and the molecular basis of their target recognition.

Figure 1

The human CREB3 subfamily of transcription factors. The bZIP domains of the members are aligned. TA: transcriptional activation domain. bZIP: basic leucine zipper domain. TM: transmembrane domain.

Figure 2

Activation of membrane-bound transcription factors of the CREB3 subfamily. CREB3 subfamily proteins are anchored to the ER membrane in an inactive form when they are not stimulated. Only upon stimulation, the CREB3 subfamily proteins are translocated by COPII vesicles from the ER to the Golgi apparatus where they will encounter S1P and S2P proteases. They are cleaved to release the N-terminal fragments which will enter the nucleus to activate transcription of target genes. CREB3 subfamily proteins might work as homodimers or heterodimers in the nucleus to activate gene expression.