BRCA1–BARD1 Regulates Axon Regeneration in Concert with the Gqα–DAG Signaling Network
In: The Journal of Neuroscience, Jg. 41 (2021-02-16), S. 2842-2853
Online
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Zugriff:
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.
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BRCA1–BARD1 Regulates Axon Regeneration in Concert with the Gqα–DAG Signaling Network
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Autor/in / Beteiligte Person: | Hanafusa, Hiroshi ; Hisamoto, Naoki ; Strahil Iv. Pastuhov ; Shimizu, Tatsuhiro ; Matsumoto, Kunihiro ; Sakai, Yoshiki |
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Zeitschrift: | The Journal of Neuroscience, Jg. 41 (2021-02-16), S. 2842-2853 |
Veröffentlichung: | Society for Neuroscience, 2021 |
Medientyp: | unknown |
ISSN: | 1529-2401 (print) ; 0270-6474 (print) |
DOI: | 10.1523/jneurosci.1806-20.2021 |
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