Mechanisms and functions of Nrf2 signaling in Drosophila

Abstract

The Nrf2 transcription factor belongs to the Cap’n’collar family, named after the founding member of this group, the product of the Drosophila cap’n’collar gene. The encoded protein, Cap’n’collar, abbreviated Cnc, offers a convenient and accessible model to study the structure, function and biology of Nrf2 transcription factors at organism, tissue, cell and molecular levels, using the powerful genetic, genomic and biochemical tools available in Drosophila. In this review we provide an account of the original identification of Cnc as a regulator of embryonic development. We will then describe the discovery of Nrf2 like-functions of Cnc and its role in acute stress signaling and aging. The establishment of Drosophila as a model organism in which the mechanisms and functions of Nrf2 signaling can be studied has led to several discoveries, the regulation of stem cell activity by an Nrf2-mediated redox mechanism, the interaction of Nrf2 with p62 and Myc in the control of tissue growth and unfolded protein response, and more. Several of these more recent lines of investigation will be highlighted. Model organisms like fly and worm remain powerful experimental platforms that can help to unravel the many remaining puzzles regarding the role of Nrf2 and its relatives in controlling the physiology and maintaining the health of multicellular organisms.

Topovectorial mechanisms control the juxtamembrane proteolytic processing of Nrf1 to remove its N-terminal polypeptides during maturation of the CNC-bZIP factor

“…However, it should be noted that such striking changes in their transactivation activity did not appear to be attributed to differences in total levels of the above-examined fusion proteins ( Figure 2B, cf. lanes [1][2][3][4][5][6][7][8][9][10]. Overall, these data demonstrate that the core h-region (aa 11-22) of TM1-adjoining NHB1 peptide, and the whole NHB2 (aa 81-106) peptide, as well as the CRAC1/2-adjoining sequence between NHB1 and NHB2, are essential for negative stepwise regulation of AD1 by NTD.…”

“…Subsequently, the recovery of p97 from its inhibitor, at the same time when newly-synthesized proteins were blocked by CHX, rendered portion of the existing ER-resident protein V5-N298-eGFP to be dynamically dislocated into the extra-luminal cytoplasmic side of membranes, in which it was allowed for the successive proteolytic digestion by 26S proteasomes and/or cleavage by other proteases through potential degrons and cleavage sites within N298. Just so a recovery of p97 from its inhibition by NMS-873 led to the release of the existing V5-N298-eGFP, subsequent turnover of its full-length ~80-kDa protein, together with its derived N-terminal polypeptides of ~55-kDa and ~12.5-kDa ( Figure 6C, lanes [5][6][7][8], was determined with their distinct half-lives estimated to be 3.25, 2.74 and 3.18 h after treatment with CHX, respectively (right graphic). By contrast, addition of MG132 (at 5 mol/L) differentially prolonged the half-lives of the ~80-kDa V5-N298-eGFP, as well as its N-terminal ~55-kDa and ~12.5-kDa polypeptides to 4.0, 3.10 and 3.34 h following CHX treatment, respectively ( Figure 6C, lanes 9-12, left graphic).…”

Rising levels of atmospheric oxygen and evolution of Nrf2

“…2). According to empirical evidence gained from Drosophila melanogaster 2728, genomic Keap1 recruitment occurred in early invertebrates preceding the divergence of the class Insecta after the Cambrian Explosion. This time frame coincides with rising levels of atmospheric O 2 during Stage 4 of the Earth’s oxygenation and matches the increased evolutionary pressure (measured by Codon-based Z-test of selection, Fig.…”

Molecular mechanisms controlling the multistage post-translational processing of endogenous Nrf1α/TCF11 proteins to yield distinct proteoforms within the coupled positive and negative feedback circuits

“…As such transcription factors are active, they play versatile roles essential for many cellular processes, including cell cycle, division, differentiation, metabolism and defence [3][4][5]. Notably, a CNC-bZIP (cap'n'collar basic-region leucine zipper) family of transcription factors comprises the Drosophila CNC protein [6], the Caenorhabditis elegans Skn-1 [7], the vertebrate NF-E2 (nuclear factor-erythroid 2) p45 subunit and related factors Nrf1 (with its long TCF11 and short Nrf1/LCR-F1 forms), Nrf2 and Nrf3 [8,9], in addition to Bach1 and Bach2 [10]. Except Skn-1, all other CNC-bZIP proteins heterodimerize with small Maf or other bZIP proteins prior to binding to antioxidant response elements (AREs) or homologous sequences in their target genes.…”