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Front Cell Neurosci. 2019 Jul 31;13:348. doi: 10.3389/fncel.2019.00348. eCollection 2019.

Functional Dissection of C. elegans bZip-Protein CEBP-1 Reveals Novel Structural Motifs Required for Axon Regeneration and Nuclear Import.

Author information

1
Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA, United States.
2
Department of Biology, Utrecht University, Utrecht, Netherlands.
3
Convergence Program of Material Science for Medicine and Pharmaceutics, Department of Life Science, Multidisciplinary Genome Institute, Hallym University, Chuncheon, South Korea.

Abstract

The basic leucine-zipper (bZIP) domain transcription factors CCAAT/enhancer-binding proteins (C/EBP) have a variety of roles in cell proliferation, differentiation, and stress response. In the nervous system, several isoforms of C/EBP function in learning and memory, neuronal plasticity, neuroinflammation, and axon regeneration. We previously reported that the Caenorhabditis elegans C/EBP homolog, CEBP-1, is essential for axon regeneration. CEBP-1 consists of 319 amino acids, with its bZIP domain at the C-terminus and a long N-terminal fragment with no known protein motifs. Here, using forward genetic screening with targeted genome editing, we have identified a unique domain in the N-terminus that is critical for its in vivo function. Additionally, we characterized three nuclear localization signals (NLS) in CEBP-1 that act together to mediate CEBP-1's nuclear import. Moreover, the Importin-α, IMA-3, can bind to CEBP-1 via one of the NLS. ima-3 is ubiquitously expressed in all somatic cells, and ima-3 null mutants are larval lethal. Using Cre-lox dependent neuron-specific deletion strategy, we show that ima-3 is not critical for axon development, but is required for axon regeneration in adults. Together, these data advance our understanding of CEBP-1's function, and suggest new regulators that remain to be identified to expand the CEBP-1 protein interactome.

KEYWORDS:

C/EBP; IMA-3; NIPI-3; Tribbles; importin; nuclear localization; structural-function domain

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