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

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.