CREB3 Transcription Factors: ER-Golgi Stress Transducers as Hubs for Cellular Homeostasis

Abstract

CREB3 family of transcription factors are ER localized proteins that belong to the bZIP family. They are transported from the ER to the Golgi, cleaved by S1P and S2P proteases and the released N-terminal domains act as transcription factors. CREB3 family members regulate the expression of a large variety of genes and according to their tissue-specific expression profiles they play, among others, roles in acute phase response, lipid metabolism, development, survival, differentiation, organelle autoregulation, and protein secretion. They have been implicated in the ER and Golgi stress responses as regulators of the cell secretory capacity and cell specific cargos. In this review we provide an overview of the diverse functions of each member of the family (CREB3, CREB3L1, CREB3L2, CREB3L3, CREB3L4) with special focus on their role in the central nervous system.

Keywords: CREB3 transcription factors; ER stress response; Golgi stress response; cellular homeostasis; central nervous system; secretory capacity; secretory pathway.

FIGURE 1

(A) CREB3 family members have a characteristic domain next to the Transactivation Domain (TAD), the adjacent to bZip Domain (ATB). The basic region, the leucine zipper and the transmembrane domain (TMD) are shown in different colors. Cleavage sites for S1P and S2P are indicated with arrows. (B) Mechanism of action: Transcription factors of the CREB3 family reside in the endoplasmic reticulum (ER) in their inactive form. After stimulation (1), they are transported from the ER to the Golgi Complex (2), where they are cleaved by S1P and S2P proteases (3) to release the N-terminal fragment. This active form then translocates to the nucleus (4) to activate transcription of their target genes (5).

FIGURE 2

Bar graph showing mouse RNA levels of the five members of the CREB3 family in different cells types from the central nervous system. Data are expressed as FPKM (Fragments per kilo base per million mapped reads). The graph was made with data extracted from a research article by Zhang et al. (2014).

FIGURE 3

Schematic representation of global functions of CREB3 proteins in the central nervous system.