期刊
AUTOPHAGY
卷 17, 期 5, 页码 1112-1130出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2020.1760623
关键词
Autophagy; CCZ1-MON1A; Amaturation; NRBF2; PI3KC3; VPS34; RAB7; trafficking
类别
资金
- Ministry of Science and Technology of the People's Republic of China [MoST-2017YFE0120100]
- National Natural Science Foundation of China [31871024, 8103487, 81773926]
- Science and Technology Development Fund, Macau SAR [024/2017/AMJ, 022/2015/A1]
- University of Macau [MYRG2019-00129-ICMS]
- Health and Medical Research Fund [17182541, 17182551]
- Shenzhen Science and Technology Innovation Commission [JCYJ20180302174028790, JCYJ201805071846 56626]
- GRF [HKBU12100618]
- Hong Kong Baptist University [RC-IRCs/17-18/03]
NRBF2, a component of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex, plays a crucial role in modulating autophagosome maturation and APP-CTF degradation by interacting with RAB7 and maintaining its activity. This study reveals a novel mechanism by which NRBF2 regulates autophagy and protein degradation associated with Alzheimer's disease.
NRBF2 is a component of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex. Our previous study has revealed its role in regulating ATG14-associated PtdIns3K activity for autophagosome initiation. In this study, we revealed an unknown mechanism by which NRBF2 modulates autophagosome maturation and APP-C-terminal fragment (CTF) degradation. Our data showed that NRBF2 localized at autolysosomes, and loss of NRBF2 impaired autophagosome maturation. Mechanistically, NRBF2 colocalizes with RAB7 and is required for generation of GTP-bound RAB7 by interacting with RAB7 GEF CCZ1-MON1A and maintaining the GEF activity. Specifically, NRBF2 regulates CCZ1-MON1A interaction with PI3KC3/VPS34 and CCZ1-associated PI3KC3 kinase activity, which are required for CCZ1-MON1A GEF activity. Finally, we showed that NRBF2 is involved in APP-CTF degradation and amyloid beta peptide production by maintaining the interaction between APP and the CCZ1-MON1A-RAB7 module to facilitate the maturation of APP-containing vesicles. Overall, our study revealed a pivotal role of NRBF2 as a new RAB7 effector in modulating autophagosome maturation, providing insight into the molecular mechanism of NRBF2-PtdIns3K in regulating RAB7 activity for macroautophagy/autophagy maturation and Alzheimer disease-associated protein degradation.
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