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: Zhanna Lipatova, Nava Segev, S. F. Zhang, Valeriya Gyurkovska

مصطلحات موضوعية: medicine.anatomical_structure, Proteasome, Membrane protein, Chemistry, Endoplasmic reticulum, Lysosome, Autophagy, Unfolded protein response, medicine, Vacuole, Endoplasmic-reticulum-associated protein degradation, Cell biology

الوصف: Thirty percent of all cellular proteins are inserted into the endoplasmic reticulum (ER), which spans throughout the cytoplasm. Two well-established stress-induced pathways ensure quality control (QC) at the ER: ER-phagy and ER-associated degradation (ERAD), which shuttle cargo for degradation to the lysosome and proteasome, respectively. In contrast, not much is known about constitutive ER-phagy. We have previously reported that excess of integral-membrane proteins is delivered from the ER to the lysosome via autophagy during normal growth of yeast cells. Here, we characterize this pathway as constitutive ER-phagy. Constitutive and stress-induced ER-phagy share the basic macro-autophagy machinery including the conserved Atgs and Ypt1 GTPase. However, induction of stress-induced autophagy is not needed for constitutive ER-phagy to occur. Moreover, the selective receptors needed for starvation-induced ER-phagy, Atg39 and Atg40, are not required for constitutive ER-phagy and neither these receptors nor their cargos are delivered through it to the vacuole. As for ERAD, while constitutive ER-phagy recognizes cargo different from that recognized by ERAD, these two ER-QC pathways can partially substitute for each other. Because accumulation of membrane proteins is associated with disease, and constitutive ER-phagy players are conserved from yeast to mammalian cells, this process could be critical for human health.Author SummaryAccumulation of excess proteins can lead to their aggregation, which in turn can cause multiple disorders, notably neurodegenerative disease. Nutritional and endoplasmic-reticulum (ER) stress stimulate autophagy and ER-associated degradation (ERAD) to clear excess and misfolded proteins, respectively. However, not much is known about clearance of excess proteins during normal growth. We have previously shown that excess integral-membrane proteins are cleared from the ER by macro-autophagy during normal growth of yeast cells. Here we characterize this pathway as constitutive ER-phagy. While this pathway shares machinery of core Atgs and autophagosomes with nutritional stress-induced ER-phagy, it differs from the latter: It is independent of the stress response and of receptors needed for stress-induced ER-phagy, and while stress-induced ER-phagy is not discriminatory, constitutive ER-phagy has specific cargos. However, when constitutive ER-phagy fails, machinery specific to stress-induced ER-phagy can process its cargo. Moreover, constitutive ER-phagy is also not dependent on ER-stress or the unfolded protein response (UPR) stimulated by this stress, although its failure elicits UPR. Finally, constitutive ER-phagy and ERAD can partially process each other’s cargo upon failure. In summary, constitutive ER-phagy, which clears excess integral-membrane proteins from the ER during normal growth does not require nutritional or ER stress for its function.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::74906c34f6bc5dbbc8360aa8e26775acTest
https://doi.org/10.1101/2020.10.21.349167Test

المؤلفون: Zulin Wu, Mengzhu Zhao, Fan Zhou, Nava Segev, Yongheng Liang

المصدر: Autophagy. 15:1653-1654

مصطلحات موضوعية: 0301 basic medicine, Autophagosome, 030102 biochemistry & molecular biology, Autophagy, Closure (topology), Cell Biology, Biology, ESCRT, Cell biology, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Assembly structure, Lysosome, medicine, Molecular Biology

الوصف: The macroautophagy/autophagy pathway includes successive steps of phagophore assembly structure formation, phagophore expansion, autophagosome (AP) closure and AP fusion with the lysosome/v...

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::9b60445e001368a5a8c7a345ed39566fTest
https://doi.org/10.1080/15548627.2019.1628547Test

المؤلفون: Zhanna Lipatova, Nava Segev

مصطلحات موضوعية: medicine.anatomical_structure, Membrane protein, Lysosome, Endoplasmic reticulum, Organelle, Autophagy, Reticulophagy, medicine, Unfolded protein response, Biology, Endoplasmic-reticulum-associated protein degradation, Cell biology

الوصف: In autophagy a cellular recycling process, excess, or damaged cellular components are shuttled to the lysosome for degradation and their resultant building blocks can be reused. Macro-autophagy, but not micro-autophagy, occurs via autophagosomes and is dependent on a conserved set of autophagy-specific proteins termed Atgs. While autophagy has been studied extensively under stress conditions, it also occurs under normal growth conditions. The endoplasmic reticulum (ER), which spans throughout the cell, is the site where newly synthesized membrane proteins and lipids are inserted into the membrane before being transported to other organelles. A rigorous quality control (QC) mechanism termed ER-associated degradation (ERAD) ensures that only properly folded proteins leave the ER, and autophagy was proposed as a backup mechanism to ERAD. Ten years ago, selective autophagy of the ER, termed ER-phagy or reticulophagy, induced by ER stress, was described in yeast. However, later it became clear that this process is independent of Atgs, and therefore belongs to the micro-autophagy type. Recently, two types of macro-ER-phagy were characterized in yeast and mammalian cells: starvation induced and QC. Here, we summarize what is currently known about the different types of ER-phagy, highlight differences between them, and discuss future questions.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::b9247534795f364b68e6f3006a7313c0Test
https://doi.org/10.1016/b978-0-12-812146-7.00010-xTest

المؤلفون: Nissim Hay, Nava Segev

المصدر: Molecular Cell. 46:4-6

مصطلحات موضوعية: chemistry.chemical_classification, Saccharomyces cerevisiae Proteins, Leucyl-tRNA synthetase, Cell, Saccharomyces cerevisiae, Cell Biology, Biology, Article, Amino acid, medicine.anatomical_structure, chemistry, Biochemistry, Leucine, medicine, Leucine-tRNA Ligase, Molecular Biology, Signal Transduction, Transcription Factors

الوصف: The target of rapamycin complex 1 (TORC1) is an essential regulator of eukaryotic cell growth that responds to growth factors, energy levels, and amino acids. The mechanisms through which the preeminent amino acid leucine signals to the TORC1-regulatory Rag GTPases, which activate TORC1 within the yeast EGO complex (EGOC) or the structurally related mammalian Rag-Ragulator complex, remain elusive. We find that the leucyl-tRNA synthetase (LeuRS) Cdc60 interacts with the Rag GTPase Gtr1 of the EGOC in a leucine-dependent manner. This interaction is necessary and sufficient to mediate leucine signaling to TORC1 and is disrupted by the engagement of Cdc60 in editing mischarged tRNA(Leu). Thus, the EGOC-TORC1 signaling module samples, via the LeuRS-intrinsic editing domain, the fidelity of tRNA(Leu) aminoacylation as a proxy for leucine availability.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b4cba3a70147ddf7cde9fb269242bd1bTest
https://doi.org/10.1016/j.molcel.2012.03.028Test

المؤلفون: Nava Segev, Zhanna Lipatova

المصدر: Cellular logistics. 4(3)

مصطلحات موضوعية: Endosome, Endocytic cycle, RAB1, Cell Biology, GTPase, Golgi apparatus, Biology, Biochemistry, Cell biology, Article Addendum, symbols.namesake, medicine.anatomical_structure, Lysosome, symbols, medicine, Molecular Medicine, Rab, Secretory pathway

الوصف: A prevailing question in the Ypt/Rab field is whether these conserved GTPases are specific to cellular compartments. The established role for Ypt1 and its human homolog Rab1 is in endoplasmic reticulum (ER)-to-Golgi transport. More recently these regulators were implicated also in autophagy. Two different TRAPP complexes, I and III, were identified as the guanine-nucleotide-exchange factors (GEFs) of Ypt1 in ER-to-Golgi transport and autophagy, respectively. Confusingly, Ypt1 and TRAPP III were also suggested to regulate endosome-to-Golgi transport, implying that they function at multiple cellular compartments, and bringing into question the nature of Ypt/Rab specificity. Recently, we showed that the role of TRAPP III and Ypt1 in autophagy occurs at the ER and that they do not regulate endosome-to-Golgi transport. Here, we discuss the significance of this conclusion to the idea that Ypt/Rabs are specific to cellular compartments. We postulate that Ypt1 regulates 2 alternative routes emanating from the ER toward the Golgi and the lysosome/vacuole. We further propose that the secretory and endocytic/lysosomal pathways intersect in 2 junctures, and 2 Ypts, Ypt1 and Ypt31, coordinate transport in the 2 intersections: Ypt1 links ER-to-Golgi and ER-to-autophagy transport, whereas Ypt31 links Golgi-to-plasma membrane (PM) transport with PM-to-Golgi recycling through endosomes.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::565f994a053d62693620c50428cf78a8Test
https://pubmed.ncbi.nlm.nih.gov/25610722Test

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

المؤلفون: Ron Dubreuil, Nava Segev

المصدر: Cellular logistics. 1(4)

مصطلحات موضوعية: biology, Phagocyte, Virulence, RAB1, Pathogenic bacteria, Cell Biology, biology.organism_classification, medicine.disease_cause, Biochemistry, DNA-binding protein, Microbiology, Cell biology, medicine.anatomical_structure, Editorial, medicine, Molecular Medicine, Secretion, Bacteria, Intracellular

الوصف: Intracellular pathogenic bacteria contrive processes in their host cell to create a niche for their own reproduction. One way that has emerged by which bacteria do that is delivery of secreted virulence factors, SVFs, to the cytoplasm of the host cells using the bacterial type IV secretion system, T4SS. These SVFs modulate the activity of their target host proteins, which in turn control key cellular processes. A major mechanism for the evolution of SVFs that modulate targets that do not exist in the bacterial kingdom is horizontal gene transfer. Recently, a number of bacterial SVFs were shown to act on two types of targets in host cells. First, a group of several SVFs modulate the activity and localization of one protein: Rab1 GTPase, a key regulator of intracellular trafficking. Second, ankyrin repeats-containing SVFs, referred to by microbiologists as Anks, interact with various binding proteins, which in turn regulate a myriad of cellular processes, including apoptosis. Modulation of trafficking and apoptosis are two examples of how invading bacteria takeover their host phagocyte, which instead of destroying the bacteria becomes a factory for its reproduction.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::68ef81b8d73c3b5dda8ff6bd0c69ea7eTest
https://pubmed.ncbi.nlm.nih.gov/22279609Test