MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes

Bujalka, Helena, Koenning, Matthias, Jackson, Stacey, Perreau, Victoria M, Pope, Berndard, Hay, Curtis M, Mitew, Stanlislaw, Hill, Andrew F ORCID: 0000-0001-5581-2354, Lu, Q Richard, Wegner, Michael, Srinivasan, Rajini, Svaren, John, Willingham, Melanie, Barres, Ben A and Emery, Ben (2013) MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. PLoS Biology, 11 (8). ISSN 1544-9173

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.

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Item type Article
URI https://vuir.vu.edu.au/id/eprint/45547
DOI 10.1371/journal.pbio.1001625
Official URL https://journals.plos.org/plosbiology/article?id=1...
Subjects Current > FOR (2020) Classification > 3209 Neurosciences
Current > Division/Research > Chancellery
Keywords oligodendrocyte progenitor cells, OPCs, vertebrate, CNS, central nervous system, protein
Citations in Scopus 168 - View on Scopus
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