Abstract 577: Beclin1 Regulates UVRAG and Rab5-Mediated Endosomal Degradation Pathway
| العنوان: | Abstract 577: Beclin1 Regulates UVRAG and Rab5-Mediated Endosomal Degradation Pathway |
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| المؤلفون: | Mark A Lampert, Åsa B. Gustafsson, Rita H. Najor, Leonardo J Leon |
| المصدر: | Circulation Research. 123 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Cell signaling, Physiology, Chemistry, Endosome, Autophagy, Organelle, Cellular homeostasis, UVRAG, Mitochondrion, Cardiology and Cardiovascular Medicine, Degradation pathway, Cell biology |
| الوصف: | Effective cellular quality control is crucial for cellular homeostasis and cardiac health. Defects in the pathways that regulate the removal of damaged proteins and organelles contribute to heart failure. Autophagy is well known for its role in removing protein aggregates and organelles; however, we recently found that the small GTPase Rab5 and early endosomes also participate in Parkin-mediated mitochondrial clearance. Beclin1 is a scaffolding protein which can form distinct PI3K protein complexes to regulate different processes. Here we have investigated the role of Beclin1 in regulating the endosomal degradation pathway in cells. Utilizing Beclin1-deficient mouse embryonic fibroblasts (MEFs), we assessed the effect of Beclin1 deficiency on endosomal activity. We found that the number of Rab5+ early endosomes were decreased, while EGF receptor levels were increased in Beclin1-/- MEFs compared to WT. This suggests that endosomal-mediated degradation is reduced in the absence of Beclin1. Moreover, the constitutively active Rab5Q79L is unable to hydrolyze bound GTP and its overexpression leads to oversized endosomes in WT cells. Interestingly, Rab5Q79L protein was unstable in Beclin1-/- MEFs and failed to induce formation of enlarged endosomes. Beclin1 has also been reported to form a complex with UVRAG, but the exact function of the Beclin1-UVRAG complex is unclear. We found that Beclin1-/- MEFs had significantly decreased UVRAG protein levels. Unexpectedly, restoration of UVRAG, but not Beclin1, restored Rab5Q79L stability in Beclin1-/- MEFs. Endogenous Rab5 levels were unaffected in Beclin1-/- MEFs after UVRAG restoration, indicating that UVRAG is required to stabilize the GTP bound active Rab5. Finally, to examine the function of Beclin1 in myocytes in vivo , we generated inducible cardiac-specific Beclin1 KO mice. Within one week of deleting Beclin1 in the adult heart, we observed significant contractile dysfunction and increased mortality. These mice also had reduced autophagic flux and significantly decreased UVRAG protein levels, but increased IGFR-beta receptor protein levels. Together, these data demonstrate the critical role of Beclin1 in cellular homeostasis as a regulator of not only autophagy but also endosomal activities. |
| تدمد: | 1524-4571 0009-7330 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::71d4f6e028893f1d8379cedab61d4741Test https://doi.org/10.1161/res.123.suppl_1.577Test |
| رقم الانضمام: | edsair.doi...........71d4f6e028893f1d8379cedab61d4741 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244571 00097330 |
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