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BRCA1/BRCA2-containing complex subunit 3 controls oligodendrocyte differentiation by dynamically regulating lysine
Chih-Yen Wang1, Benjamin Deneen2, Shun-Fen Tzeng1
1Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
Glia
|June 12, 2019
Summary
Lys63-linked ubiquitination (K63Ub) and BRCA1/BRCA2-containing complex subunit 3 (BRCC3)-mediated deubiquitination are crucial for oligodendrocyte differentiation and myelin protein trafficking in the central nervous system (CNS).
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Oligodendrocytes (OLs) are vital for central nervous system (CNS) function, forming myelin sheaths around axons.
- OL differentiation and maturation involve strict regulation of myelin protein and membrane metabolism.
- The roles of ubiquitination and deubiquitination systems in OL development are not fully understood.
Purpose of the Study:
- To investigate the function of Lys63-linked ubiquitination (K63Ub) and K63-specific deubiquitination (DUB) systems, regulated by BRCC3, during OL differentiation.
- To elucidate the involvement of these systems in the cellular trafficking of myelin proteins.
Main Methods:
- Oligodendrocyte precursor cells (OPCs) were manipulated using mutant ubiquitin (K63R) overexpression and BRCC3 knockdown (BRCC3-KD) via shRNA.
- Immunoprecipitation assays were used to detect protein associations and cellular localization.
- In vivo studies involved cuprizone-induced demyelination in rats and analysis of human multiple sclerosis (MS) tissues.
Main Results:
- Inhibition of K63Ub led to upregulation of myelin basic protein (MBP) and proteolipid protein (PLP).
- BRCC3 knockdown suppressed OL differentiation, decreasing MBP and PLP levels and increasing sphingolipid GalC, MBP, and PLP in endosomal/lysosomal compartments.
- Impaired OL differentiation was observed in BRCC3-KD rats, and human MS lesions showed reduced BRCC3 and increased EEA1/K63Ub expression in OLs.
Conclusions:
- The balance between K63Ub and BRCC3-mediated DUB is essential for myelin protein trafficking and OL differentiation.
- Dysregulation of these systems may contribute to demyelinating diseases like multiple sclerosis.
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