BRCA1–BARD1 Regulates Axon Regeneration in Concert with the Gqα–DAG Signaling Network
| Autor: | Hiroshi Hanafusa, Naoki Hisamoto, Strahil Iv. Pastuhov, Tatsuhiro Shimizu, Kunihiro Matsumoto, Yoshiki Sakai |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Diacylglycerol Kinase Ubiquitin-Protein Ligases BRCA1-BARD1 Animals Genetically Modified 03 medical and health sciences 0302 clinical medicine BARD1 Chlorocebus aethiops medicine Animals Amino Acid Sequence Axon Caenorhabditis elegans Caenorhabditis elegans Proteins Mitosis Research Articles Diacylglycerol kinase biology Chemistry Tumor Suppressor Proteins General Neuroscience Regeneration (biology) axon regeneration biology.organism_classification Axons Nerve Regeneration Cell biology Ubiquitin ligase 030104 developmental biology medicine.anatomical_structure COS Cells biology.protein GTP-Binding Protein alpha Subunits Gq-G11 Signal transduction 030217 neurology & neurosurgery Signal Transduction Cellular/Molecular |
| Zdroj: | The Journal of Neuroscience |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.1806-20.2021 |
| Popis: | The breast cancer susceptibility protein BRCA1 and its partner BRCA1-associated RING domain protein 1 (BARD1) form an E3-ubiquitin (Ub) ligase complex that acts as a tumor suppressor in mitotic cells. However, the roles of BRCA1–BARD1 in postmitotic cells, such as neurons, remain poorly defined. Here, we report that BRC-1 and BRD-1, theCaenorhabditis elegansorthologs of BRCA1 and BARD1, are required for adult-specific axon regeneration, which is positively regulated by the EGL-30 Gqα–diacylglycerol (DAG) signaling pathway. This pathway is downregulated by DAG kinase (DGK), which converts DAG to phosphatidic acid (PA). We demonstrate that inactivation of DGK-3 suppresses thebrc-1 brd-1defect in axon regeneration, suggesting that BRC-1–BRD-1 inhibits DGK-3 function. Indeed, we show that BRC-1–BRD-1 poly-ubiquitylates DGK-3 in a manner dependent on its E3 ligase activity, causing DGK-3 degradation. Furthermore, we find that axon injury causes the translocation of BRC-1 from the nucleus to the cytoplasm, where DGK-3 is localized. These results suggest that the BRC-1–BRD-1 complex regulates axon regeneration in concert with the Gqα–DAG signaling network. Thus, this study describes a new role for breast cancer proteins in fully differentiated neurons and the molecular mechanism underlying the regulation of axon regeneration in response to nerve injury.SIGNIFICANCE STATEMENTBRCA1–BRCA1-associated RING domain protein 1 (BARD1) is an E3-ubiquitin (Ub) ligase complex acting as a tumor suppressor in mitotic cells. The roles of BRCA1–BARD1 in postmitotic cells, such as neurons, remain poorly defined. We show here thatCaenorhabditis elegansBRC-1/BRCA1 and BRD-1/BARD1 are required for adult-specific axon regeneration, a process that requires high diacylglycerol (DAG) levels in injured neurons. The DAG kinase (DGK)-3 inhibits axon regeneration by reducing DAG levels. We find that BRC-1–BRD-1 poly-ubiquitylates and degrades DGK-3, thereby keeping DAG levels elevated and promoting axon regeneration. Furthermore, we demonstrate that axon injury causes the translocation of BRC-1 from the nucleus to the cytoplasm, where DGK-3 is localized. Thus, this study describes a new role for BRCA1–BARD1 in fully-differentiated neurons. |
| Databáze: | OpenAIRE |
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