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 Biology

مصطلحات 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

المؤلفون: Nava Segev

المصدر: PLoS Genetics, Vol 16, Iss 3, p e1008631 (2020)
PLoS Genetics

مصطلحات 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

المؤلفون: Zhanna Lipatova, Jonathan W. Mulholland, Nava Segev, Ankur H. Shah, Jane J. Kim

المصدر: Molecular Biology of the Cell

مصطلحات موضوعية: Saccharomyces cerevisiae Proteins, Golgi Apparatus, GTPase, Saccharomyces cerevisiae, Biology, Endoplasmic Reticulum, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Lysosome, Gene Expression Regulation, Fungal, medicine, Autophagy, Molecular Biology, 030304 developmental biology, 0303 health sciences, Endoplasmic reticulum, Membrane Proteins, Cell Biology, Articles, Golgi apparatus, Cell biology, Transport protein, Protein Transport, medicine.anatomical_structure, rab GTP-Binding Proteins, Membrane Trafficking, Mutation, Proteolysis, symbols, Unfolded protein response, Rab, Lysosomes, 030217 neurology & neurosurgery

الوصف: Ypt1 GTPase, in the context of an autophagy-specific module, regulates ER-phagy. Because Ypt1 is a known regulator of ER-to-Golgi transport, this means that a single Ypt/Rab can regulate two alternative transport steps from one compartment, the ER, to two different destinations, the Golgi and the autophagy pathway.
Accumulation of misfolded proteins on intracellular membranes has been implicated in neurodegenerative diseases. One cellular pathway that clears such aggregates is endoplasmic reticulum autophagy (ER-phagy), a selective autophagy pathway that delivers excess ER to the lysosome for degradation. Not much is known about the regulation of ER-phagy. The conserved Ypt/Rab GTPases regulate all membrane trafficking events in eukaryotic cells. We recently showed that a Ypt module, consisting of Ypt1 and autophagy-specific upstream activator and downstream effector, regulates the onset of selective autophagy in yeast. Here we show that this module acts at the ER. Autophagy-specific mutations in its components cause accumulation of excess membrane proteins on aberrant ER structures and induction of ER stress. This accumulation is due to a block in transport of these membranes to the lysosome, where they are normally cleared. These findings establish a role for an autophagy-specific Ypt1 module in the regulation of ER-phagy. Moreover, because Ypt1 is a known key regulator of ER-to-Golgi transport, these findings establish a second role for Ypt1 at the ER. We therefore propose that individual Ypt/Rabs, in the context of distinct modules, can coordinate alternative trafficking steps from one cellular compartment to different destinations.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1484d74c6534006210bb0a7ffbde1d9fTest
https://pubmed.ncbi.nlm.nih.gov/23924895Test