دورية أكاديمية
p27 controls autophagic vesicle trafficking in glucose-deprived cells via the regulation of ATAT1-mediated microtubule acetylation.
| العنوان: | p27 controls autophagic vesicle trafficking in glucose-deprived cells via the regulation of ATAT1-mediated microtubule acetylation. |
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| المؤلفون: | Nowosad, Ada, Creff, Justine, Jeannot, Pauline, Culerrier, Raphael, Codogno, Patrice, Manenti, Stephane, Nguyen, Laurent, Besson, Arnaud |
| المصدر: | Cell Death and Disease, 12 (5), 481 (2021) |
| بيانات النشر: | Springer Nature, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Microtubule Proteins, Microtubule-Associated Proteins, Proliferating Cell Nuclear Antigen, p27 antigen, Acetyltransferases, ATAT1 protein, mouse, Acetylation, Acetyltransferases/metabolism, Animals, Autophagy/physiology, Humans, Mice, Microtubule Proteins/metabolism, Microtubule-Associated Proteins/metabolism, Microtubules/metabolism, Proliferating Cell Nuclear Antigen/metabolism, Signal Transduction, Autophagy, Microtubules, Immunology, Cellular and Molecular Neuroscience, Cell Biology, Cancer Research, Life sciences, Biochemistry, biophysics & molecular biology, Sciences du vivant, Biochimie, biophysique & biologie moléculaire |
| الوصف: | The cyclin-dependent kinase inhibitor p27Kip1 (p27) has been involved in promoting autophagy and survival in conditions of metabolic stress. While the signaling cascade upstream of p27 leading to its cytoplasmic localization and autophagy induction has been extensively studied, how p27 stimulates the autophagic process remains unclear. Here, we investigated the mechanism by which p27 promotes autophagy upon glucose deprivation. Mouse embryo fibroblasts (MEFs) lacking p27 exhibit a decreased autophagy flux compared to wild-type cells and this is correlated with an abnormal distribution of autophagosomes. Indeed, while autophagosomes are mainly located in the perinuclear area in wild-type cells, they are distributed throughout the cytoplasm in p27-null MEFs. Autophagosome trafficking towards the perinuclear area, where most lysosomes reside, is critical for autophagosome-lysosome fusion and cargo degradation. Vesicle trafficking is mediated by motor proteins, themselves recruited preferentially to acetylated microtubules, and autophagy flux is directly correlated to microtubule acetylation levels. p27-/- MEFs exhibit a marked reduction in microtubule acetylation levels and restoring microtubule acetylation in these cells, either by re-expressing p27 or with deacetylase inhibitors, restores perinuclear positioning of autophagosomes and autophagy flux. Finally, we find that p27 promotes microtubule acetylation by binding to and stabilizing α-tubulin acetyltransferase (ATAT1) in glucose-deprived cells. ATAT1 knockdown results in random distribution of autophagosomes in p27+/+ MEFs and impaired autophagy flux, similar to that observed in p27-/- cells. Overall, in response to glucose starvation, p27 promotes autophagy by facilitating autophagosome trafficking along microtubule tracks by maintaining elevated microtubule acetylation via an ATAT1-dependent mechanism. |
| نوع الوثيقة: | journal article http://purl.org/coar/resource_type/c_6501Test article peer reviewed |
| اللغة: | English |
| العلاقة: | http://www.nature.com/articles/s41419-021-03759-9.pdfTest; https://doi.org/10.1038/s41419-021-03759-9Test; urn:issn:2041-4889 |
| DOI: | 10.1038/s41419-021-03759-9 |
| الوصول الحر: | https://orbi.uliege.be/handle/2268/304785Test |
| حقوق: | open access http://purl.org/coar/access_right/c_abf2Test info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsorb.304785 |
| قاعدة البيانات: | ORBi |
| DOI: | 10.1038/s41419-021-03759-9 |
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