MYRF Is a Membrane-Associated Transcription Factor That Autoproteolytically Cleaves to Directly Activate Myelin Genes

Helena Bujalka, Matthias Koenning, Stacey Jackson, Victoria M. Perreau, Bernard Pope, Curtis M. Hay, Stanlislaw Mitew, Andrew F. Hill, Q. Richard Lu, Michael Wegner, Rajini Srinivasan, John Svaren, Melanie Willingham, Ben A. Barres, Ben Emery

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

The myelination of axons is a crucial step during vertebrate central nervous system (CNS) development, allowing for rapid and energy efficient saltatory conduction of nerve impulses. Accordingly, the differentiation of oligodendrocytes, the myelinating cells of the CNS, and their expression of myelin genes are under tight transcriptional control. We previously identified a putative transcription factor, Myelin Regulatory Factor (Myrf), as being vital for CNS myelination. Myrf is required for the generation of CNS myelination during development and also for its maintenance in the adult. It has been controversial, however, whether Myrf directly regulates transcription, with reports of a transmembrane domain and lack of nuclear localization. Here we show that Myrf is a membrane-associated transcription factor that undergoes an activating proteolytic cleavage to separate its transmembrane domain-containing C-terminal region from a nuclear-targeted N-terminal region. Unexpectedly, this cleavage event occurs via a protein domain related to the autoproteolytic intramolecular chaperone domain of the bacteriophage tail spike proteins, the first time this domain has been found to play a role in eukaryotic proteins. Using ChIP-Seq we show that the N-terminal cleavage product directly binds the enhancer regions of oligodendrocyte-specific and myelin genes. This binding occurs via a defined DNA-binding consensus sequence and strongly promotes the expression of target genes. These findings identify Myrf as a novel example of a membrane-associated transcription factor and provide a direct molecular mechanism for its regulation of oligodendrocyte differentiation and CNS myelination.

Original languageEnglish (US)
Article numbere1001625
JournalPLoS biology
Volume11
Issue number8
DOIs
StatePublished - Aug 2013

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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    Bujalka, H., Koenning, M., Jackson, S., Perreau, V. M., Pope, B., Hay, C. M., Mitew, S., Hill, A. F., Lu, Q. R., Wegner, M., Srinivasan, R., Svaren, J., Willingham, M., Barres, B. A., & Emery, B. (2013). MYRF Is a Membrane-Associated Transcription Factor That Autoproteolytically Cleaves to Directly Activate Myelin Genes. PLoS biology, 11(8), [e1001625]. https://doi.org/10.1371/journal.pbio.1001625