NFE2L3 (NRF3): the Cinderella of the Cap'n'Collar transcription factors

Abstract

NFE2L3 [Nuclear factor (erythroid-derived 2)-like 3] or NRF3, a member of the Cap'n'Collar (CNC) family, is a basic-region leucine zipper (bZIP) transcription factor that was first identified over 10 years ago. Contrary to its extensively studied homolog NFE2L2 (NRF2), the regulation and function of the NFE2L3 protein have not yet attracted as much attention. Nevertheless, several recent reports have now shed light on the possible roles of NFE2L3. Structural and biochemical studies revealed a series of domains and modifications that are critical for its cellular regulation. The control of the subcellular localization of NFE2L3 appears to be essential for understanding its role in various cellular processes. Importantly, newer studies provide fascinating insights linking NFE2L3 to differentiation, inflammation, and carcinogenesis. Here, we present an overview of the current level of knowledge of NFE2L3 transcription factor biology in humans and mice. From being the Cinderella of the CNC transcription factors for many years, NFE2L3 may now rapidly come into its own.

Fig. 1

Structure of the human NFE2L3 transcription factor. NHB1 N-terminal homology box 1, NHB2 N-terminal homology box 2, PEST PEST domain, N potential N-glycosylation sites, transactivation domain, transactivation domain as defined by Gal4-luciferase reporter studies, CNC domain Cap‘n’Collar homology domain, basic domain basic DNA-binding domain, leucine zipper leucine zipper dimerization domain

Fig. 2

Comparison of human CNC transcription factor sequences. Alignment of human p45 NFE2, NFE2L1, NFE2L2, NFE2L3, BACH1, and BACH2 protein sequences was performed using ClustalW program [117]. Identical residues are shaded in grey. The basic region (in light blue) and the CNC domain (in orange) are indicated. Asterisks indicate leucine zipper residues

Fig. 3

Cross-species comparison of NFE2L3 sequences. Protein sequences of NFE2L3 from nine different species were aligned using ClustalW program [117]. Identical residues are shaded in grey. The basic region (in light blue), the CNC domain (in orange), the NHB1 domain (in purple), the NHB2 domain (in light green) and the PEST motif (in black) are indicated. Asterisks indicate leucine zipper residues

Fig. 4

Proposed model for NFE2L3 regulation. Hypothetical model to describe the cellular regulation of NFE2L3 based on published literature. Once activated by a stimulus (e.g., TNF), transcription of NFE2L3 gene occurs in the nucleus leading to the production of NFE2L3 RNA in the nucleus and then to the translation in the cytosol into a ‘B’ form of NFE2L3 protein. The ‘B’ form can be targeted to the ER where it is N-glycosylated to become the A form of NFE2L3. The ‘A’ and/or ‘B’ forms of NFE2L3 is (are) hypothesized to be cleaved at the N-terminal end into a ‘C’ form, which is mainly found in the nucleus. The ‘C’ form is considered to be the major active form of NFE2L3 heterodimerizing with small Maf proteins. The resulting heterodimers activate transcription of their target genes through binding to specific DNA-binding sites including ARE, MARE, NFE2, StreB/EpRE sequences. The NFE2L3 ‘A’, ‘B’, and ‘C’ forms have short half-lives and are most likely degraded through the ubiquitin–proteasome pathway in the cytosol and/or in the nucleus