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المؤلفون: Jing Zhu, Hui Xu, Yanhong Xue, Rakhilya Murtazina, Liangyi Chen, Wenjing Li, Rui Li, Yongheng Liang, Haiqian Xu, Liuju Li, Zhiping Xie, Juan Cai, Ao Zhang, Mengzhu Zhao, Xiaoshuai Huang, Qunli Li, Zulin Wu, Yi Ting Zhou, Xiaoxia Cong, Nava Segev, Valeriya Gyurkovska, Dan Sun, Fan Zhou, Lei Zhao
المصدر: Autophagy
The Journal of Cell Biologyمصطلحات موضوعية: Autophagosome, Saccharomyces cerevisiae Proteins, Endosome, Endocytic cycle, Autophagy-Related Proteins, Endosomes, Saccharomyces cerevisiae, macromolecular substances, Biology, Article, ESCRT, 03 medical and health sciences, 0302 clinical medicine, Lysosome, Autophagy, medicine, Research Articles, rab5 GTP-Binding Proteins, 030304 developmental biology, 0303 health sciences, Endosomal Sorting Complexes Required for Transport, Autophagosomes, Intracellular Membranes, Cell Biology, Transport protein, Cell biology, ESCRT complex, Protein Transport, medicine.anatomical_structure, Vacuoles, Commentary, Lysosomes, 030217 neurology & neurosurgery
الوصف: Zhou et al. identify the mechanism of autophagosome (AP) closure. They show that Rab5 GTPase regulates an interaction between the ESCRT subunit Snf7 and Atg17 to bring ESCRT to APs where it catalyzes AP closure. These findings highlight the convergence of the endocytic and autophagic pathways at this step.
In the conserved autophagy pathway, autophagosomes (APs) engulf cellular components and deliver them to the lysosome for degradation. Before fusing with the lysosome, APs have to close via an unknown mechanism. We have previously shown that the endocytic Rab5-GTPase regulates AP closure. Therefore, we asked whether ESCRT, which catalyzes scission of vesicles into late endosomes, mediates the topologically similar process of AP sealing. Here, we show that depletion of representative subunits from all ESCRT complexes causes late autophagy defects and accumulation of APs. Focusing on two subunits, we show that Snf7 and the Vps4 ATPase localize to APs and their depletion results in accumulation of open APs. Moreover, Snf7 and Vps4 proteins complement their corresponding mutant defects in vivo and in vitro. Finally, a Rab5-controlled Atg17–Snf7 interaction is important for Snf7 localization to APs. Thus, we unravel a mechanism in which a Rab5-dependent Atg17–Snf7 interaction leads to recruitment of ESCRT to open APs where ESCRT catalyzes AP closure.الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e4f388fa8467bed00c6cf9a8d6685d27Test
https://doi.org/10.1083/jcb.201811173Test -
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المؤلفون: Nava Segev
المصدر: PLoS Genetics, Vol 16, Iss 3, p e1008631 (2020)
PLoS Geneticsمصطلحات موضوعية: Cancer Research, Physiology, AMP-Activated Protein Kinases, QH426-470, Biochemistry, 0302 clinical medicine, Fluorescence Microscopy, AMP-activated protein kinase, Medicine and Health Sciences, Homeostasis, Proteasome endopeptidase complex, Genetics (clinical), 0303 health sciences, Microscopy, biology, Cell Death, Organic Compounds, Monosaccharides, Eukaryota, Light Microscopy, Cell biology, Chemistry, Immunoblot Analysis, medicine.anatomical_structure, Cell Processes, Physical Sciences, Cellular Structures and Organelles, Research Article, Proteasome Endopeptidase Complex, Autophagic Cell Death, Carbohydrates, Molecular Probe Techniques, Research and Analysis Methods, 03 medical and health sciences, Lysosome, medicine, Genetics, Microautophagy, Molecular Biology Techniques, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Endosomal Sorting Complexes Required for Transport, Endoplasmic reticulum, Organic Chemistry, Chemical Compounds, Organisms, Fungi, Biology and Life Sciences, Proteins, Protein Complexes, Proteasomes, Cell Biology, Yeast, Glucose, Proteasome, Cytoplasm, Vacuoles, biology.protein, Lysosomes, Physiological Processes, 030217 neurology & neurosurgery
الوصف: The ubiquitin-proteasome system regulates numerous cellular processes and is central to protein homeostasis. In proliferating yeast and many mammalian cells, proteasomes are highly enriched in the nucleus. In carbon-starved yeast, proteasomes migrate to the cytoplasm and collect in proteasome storage granules (PSGs). PSGs dissolve and proteasomes return to the nucleus within minutes of glucose refeeding. The mechanisms by which cells regulate proteasome homeostasis under these conditions remain largely unknown. Here we show that AMP-activated protein kinase (AMPK) together with endosomal sorting complexes required for transport (ESCRTs) drive a glucose starvation-dependent microautophagy pathway that preferentially sorts aberrant proteasomes into the vacuole, thereby biasing accumulation of functional proteasomes in PSGs. The proteasome core particle (CP) and regulatory particle (RP) are regulated differently. Without AMPK, the insoluble protein deposit (IPOD) serves as an alternative site that specifically sequesters CP aggregates. Our findings reveal a novel AMPK-controlled ESCRT-mediated microautophagy mechanism in the regulation of proteasome trafficking and homeostasis under carbon starvation.
Author summary Protein homeostasis is critical for maintaining organismal health. The cellular dysfunction caused by accumulation and aggregation of aberrant proteins or other normally short-lived proteins is associated with aging and many human diseases, including neurodegenerative disorders, diabetes, and various types of cancer. The eukaryotic ubiquitin-proteasome system regulates numerous cellular processes and through selective protein degradation helps maintain cellular protein homeostasis under normal growth conditions. However, hundreds of cellular granules or condensates are formed during carbon starvation in yeast cells, including proteasome storage granules (PSGs). PSGs result from a massive relocation of proteasomes from the nucleus to the cytoplasm under these conditions. However, how cells regulate proteasome homeostasis under these conditions remains largely unknown. Here, we demonstrate that AMPK (AMP-activated protein kinase), a master cellular energy regulator, drives ESCRT (endosomal sorting complexes required for transport)-dependent microautophagy of aberrant proteasomes. This allows rapid re-mobilization of functional proteasomes from PSGs upon glucose refeeding. Previous studies had identified classical macroautophagy as a means of degrading proteasomes during starvation. Our work shows that direct uptake of proteasomes into the vacuole (lysosome) by microautophagy is a major means of proteasome elimination under limiting glucose conditions.الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3f7b24da07c39bca56371981d7aa4875Test
https://doaj.org/article/2a488a1e85c24a68be52664af1becbc9Test