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

被引:190
作者
Bujalka, Helena [1 ,2 ]
Koenning, Matthias [1 ,2 ]
Jackson, Stacey [1 ,2 ]
Perreau, Victoria M. [1 ,2 ]
Pope, Bernard [3 ,4 ]
Hay, Curtis M. [1 ,2 ]
Mitew, Stanlislaw [1 ,2 ]
Hill, Andrew F. [5 ]
Lu, Q. Richard [6 ,7 ]
Wegner, Michael [8 ]
Srinivasan, Rajini [9 ]
Svaren, John [9 ]
Willingham, Melanie [1 ,2 ]
Barres, Ben A. [10 ]
Emery, Ben [1 ,2 ,11 ]
机构
[1] Univ Melbourne, Dept Anat & Neurosci, Parkville, Vic 3052, Australia
[2] Univ Melbourne, Neurosci Res Ctr, Parkville, Vic 3052, Australia
[3] Univ Melbourne, Dept Comp & Informat Syst, Parkville, Vic 3052, Australia
[4] Univ Melbourne, VLSCI, Parkville, Vic 3052, Australia
[5] Univ Melbourne, Dept Biochem & Mol Biol, Mol Sci & Biotechnol Inst Bio21, Parkville, Vic 3052, Australia
[6] Univ Texas Austin, Dept Dev Biol, Austin, TX 78712 USA
[7] Univ Texas Austin, Kent Waldrep Fdn Ctr Basic Neurosci Res Nerve Gro, Austin, TX 78712 USA
[8] Univ Erlangen Nurnberg, Inst Biochem, Nurnberg, Germany
[9] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA
[10] Stanford Univ, Dept Neurobiol, Stanford, CA 94305 USA
[11] Florey Inst Neurosci & Mental Hlth, Parkville, Vic, Australia
基金
澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;
关键词
CRYSTAL-STRUCTURE; TRANSMEMBRANE PROTEIN; REGULATORY FACTOR; OLIGODENDROCYTES; DATABASE; DOMAIN; PREDICTION; BRAIN; DIFFERENTIATION; PROTEOLYSIS;
D O I
10.1371/journal.pbio.1001625
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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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页数:15
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