scholarly journals Characterisation of the Ubiquitin-ESCRT pathway in Asgard archaea sheds new light on origins of membrane trafficking in eukaryotes

2021 ◽  
Author(s):  
Tomoyuki Hatano ◽  
Saravanan Palani ◽  
Dimitra Papatziamou ◽  
Diorge P. Souza ◽  
Ralf Salzer ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Critical Role ◽  
Extracellular Vesicle ◽  
Eukaryotic Cells ◽  
Vesicle Formation ◽  
Membrane Repair ◽  
Escrt Machinery ◽  
Viral Egress ◽  
Eukaryotic Origin ◽  
Genome Assemblies

SUMMARYThe ESCRT machinery performs a critical role in membrane remodelling events in all eukaryotic cells, including in membrane trafficking, membrane repair, cytokinetic abscission, in viral egress, and in the generation of extracellular vesicles. While the machinery is complex in modern day eukaryotes, where it comprises dozens of proteins, the system has simpler and more ancient origins. Indeed, homologues of ESCRT-III and the Vps4 ATPase, the proteins that execute the final membrane scission reaction, play analogous roles in cytokinesis and potentially in extracellular vesicle formation in TACK archaea where ESCRT-I and II homologues seem to be absent. Here, we explore the phylogeny, structure, and biochemistry of homologues of the ESCRT machinery and the associated ubiquitylation system found in genome assemblies of the recently discovered Asgard archaea. In these closest living prokaryotic relatives of eukaryotes, we provide evidence for the ESCRT-I and II sub-complexes being involved in the ubiquitin-directed recruitment of ESCRT-III,_as it is in eukaryotes. This analysis suggests a pre-eukaryotic origin for the Ub-coupled ESCRT system and a likely path of ESCRT evolution via a series of gene duplication and diversification events.

scholarly journals Atg19 Mediates a Dual Interaction Cargo Sorting Mechanism in Selective Autophagy

2007 ◽  
Vol 18 (3) ◽  
pp. 919-929 ◽  
Author(s):  
Chiung-Ying Chang ◽  
Wei-Pang Huang
Keyword(s):  
Membrane Trafficking ◽  
Eukaryotic Cells ◽  
Vesicle Formation ◽  
Double Knockout ◽  
Yeast Saccharomyces Cerevisiae ◽  
Selective Autophagy ◽  
Atg Proteins ◽  
Transport Vesicles ◽  
Efficient Delivery ◽  
Transport Defect

Autophagy is a catabolic membrane-trafficking mechanism conserved in all eukaryotic cells. In addition to the nonselective transport of bulk cytosol, autophagy is responsible for efficient delivery of the vacuolar enzyme Ape1 precursor (prApe1) in the budding yeast Saccharomyces cerevisiae, suggesting the presence of a prApe1 sorting machinery. Sequential interactions between Atg19-Atg11 and Atg19-Atg8 pairs are thought responsible for targeting prApe1 to the vesicle formation site, the preautophagosomal structure (PAS), and loading it into transport vesicles, respectively. However, the different patterns of prApe1 transport defect seen in the atg11Δ and atg19Δ strains seem to be incompatible with this model. Here we report that prApe1 could not be targeted to the PAS and failed to be delivered into the vacuole in atg8Δ atg11Δ double knockout cells regardless of the nutrient conditions. We postulate that Atg19 mediates a dual interaction prApe1-sorting mechanism through independent, instead of sequential, interactions with Atg11 and Atg8. In addition, to efficiently deliver prApe1 to the vacuole, a proper interaction between Atg11 and Atg9 is indispensable. We speculate that Atg11 may elicit a cargo-loading signal and induce Atg9 shuttling to a specific PAS site, where Atg9 relays the signal and recruits other Atg proteins to induce vesicle formation.

scholarly journals Annexin A2 in Fibrinolysis, Inflammation and Fibrosis

2021 ◽  
Vol 22 (13) ◽  
pp. 6836
Author(s):  
Hana I. Lim ◽  
Katherine A. Hajjar
Keyword(s):  
Cell Surface ◽  
Tissue Injury ◽  
Critical Role ◽  
Annexin A2 ◽  
Hemorrhagic Disease ◽  
Membrane Repair ◽  
Endothelial Cell Surface ◽  
Human Disorders ◽  
A Cell ◽  
Organ Fibrosis

As a cell surface tissue plasminogen activator (tPA)-plasminogen receptor, the annexin A2 (A2) complex facilitates plasmin generation on the endothelial cell surface, and is an established regulator of hemostasis. Whereas A2 is overexpressed in hemorrhagic disease such as acute promyelocytic leukemia, its underexpression or impairment may result in thrombosis, as in antiphospholipid syndrome, venous thromboembolism, or atherosclerosis. Within immune response cells, A2 orchestrates membrane repair, vesicle fusion, and cytoskeletal organization, thus playing a critical role in inflammatory response and tissue injury. Dysregulation of A2 is evident in multiple human disorders, and may contribute to the pathogenesis of various inflammatory disorders. The fibrinolytic system, moreover, is central to wound healing through its ability to remodel the provisional matrix and promote angiogenesis. A2 dysfunction may also promote tissue fibrogenesis and end-organ fibrosis.

scholarly journals Regulation of intracellular membrane trafficking and cell dynamics by syntaxin-6

2012 ◽  
Vol 32 (4) ◽  
pp. 383-391 ◽  
Author(s):  
Jae-Joon Jung ◽  
Shivangi M. Inamdar ◽  
Ajit Tiwari ◽  
Amit Choudhury
Keyword(s):  
Membrane Trafficking ◽  
Critical Role ◽  
Cell Types ◽  
Intracellular Membrane ◽  
Cellular Functions ◽  
Cell Dynamics ◽  
Transport Pathways ◽  
Protein Receptor ◽  
Secretory Transport ◽  
Target Membrane

Intracellular membrane trafficking along endocytic and secretory transport pathways plays a critical role in diverse cellular functions including both developmental and pathological processes. Briefly, proteins and lipids destined for transport to distinct locations are collectively assembled into vesicles and delivered to their target site by vesicular fusion. SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) proteins are required for these events, during which v-SNAREs (vesicle SNAREs) interact with t-SNAREs (target SNAREs) to allow transfer of cargo from donor vesicle to target membrane. Recently, the t-SNARE family member, syntaxin-6, has been shown to play an important role in the transport of proteins that are key to diverse cellular dynamic processes. In this paper, we briefly discuss the specific role of SNAREs in various mammalian cell types and comprehensively review the various roles of the Golgi- and endosome-localized t-SNARE, syntaxin-6, in membrane trafficking during physiological as well as pathological conditions.

scholarly journals Membrane Repair: Mechanisms and Pathophysiology

2015 ◽  
Vol 95 (4) ◽  
pp. 1205-1240 ◽  
Author(s):  
Sandra T. Cooper ◽  
Paul L. McNeil
Keyword(s):  
Molecular Mechanisms ◽  
Eukaryotic Cells ◽  
Membrane Repair ◽  
Membrane Pore ◽  
Rapid Repair ◽  
Repair Mechanisms ◽  
Molecular Machinery ◽  
Repair Pathways ◽  
Different Tissues ◽  
Ischemic Stress

Eukaryotic cells have been confronted throughout their evolution with potentially lethal plasma membrane injuries, including those caused by osmotic stress, by infection from bacterial toxins and parasites, and by mechanical and ischemic stress. The wounded cell can survive if a rapid repair response is mounted that restores boundary integrity. Calcium has been identified as the key trigger to activate an effective membrane repair response that utilizes exocytosis and endocytosis to repair a membrane tear, or remove a membrane pore. We here review what is known about the cellular and molecular mechanisms of membrane repair, with particular emphasis on the relevance of repair as it relates to disease pathologies. Collective evidence reveals membrane repair employs primitive yet robust molecular machinery, such as vesicle fusion and contractile rings, processes evolutionarily honed for simplicity and success. Yet to be fully understood is whether core membrane repair machinery exists in all cells, or whether evolutionary adaptation has resulted in multiple compensatory repair pathways that specialize in different tissues and cells within our body.

scholarly journals Regulation of Rab5 Function during Phagocytosis of Live Pseudomonas aeruginosa in Macrophages

2013 ◽  
Vol 81 (7) ◽  
pp. 2426-2436 ◽  
Author(s):  
Sushmita Mustafi ◽  
Nathalie Rivero ◽  
Joan C. Olson ◽  
Philip D. Stahl ◽  
M. Alejandro Barbieri
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Membrane Trafficking ◽  
Rho Gtpase ◽  
Critical Role ◽  
Rab Gtpases ◽  
Content Type ◽  
Host Cell Proteins ◽  
Opportunistic Human Pathogen ◽  
Hospital Acquired ◽  
Adp Ribosyltransferase

ABSTRACTPseudomonas aeruginosa, a Gram-negative opportunistic human pathogen, is a frequent cause of severe hospital-acquired infections. Effectors produced by the type III secretion system disrupt mammalian cell membrane trafficking and signaling and are integral to the establishment ofP. aeruginosainfection. One of these effectors, ExoS, ADP-ribosylates several host cell proteins, including Ras and Rab GTPases. In this study, we demonstrated that Rab5 plays a critical role during early stages ofP. aeruginosainvasion of J774-Eclone macrophages. We showed that live, but not heat-inactivated,P. aeruginosainhibited phagocytosis and that this occurred in conjunction with downregulation of Rab5 activity. Inactivation of Rab5 was dependent on ExoS ADP-ribosyltransferase activity, and in J744-Eclone cells, ExoS ADP-ribosyltransferase activity caused a more severe inhibition of phagocytosis than ExoS Rho GTPase activity. Furthermore, we found that expression of Rin1, a Rab5 guanine exchange factor, but not Rabex5 and Rap6, partially reversed the inactivation of Rab5 during invasion of liveP. aeruginosa. These studies provide evidence that liveP. aeruginosacells are able to influence their rate of phagocytosis in macrophages by directly regulating activation of Rab5.

Organelle morphogenesis by active membrane remodeling

Soft Matter ◽  
2015 ◽  
Vol 11 (12) ◽  
pp. 2387-2393 ◽  
Author(s):  
N. Ramakrishnan ◽  
John H. Ipsen ◽  
Madan Rao ◽  
P. B. Sunil Kumar
Keyword(s):  
Membrane Trafficking ◽  
Eukaryotic Cells ◽  
Membrane Remodeling ◽  
Active Membrane ◽  
Internal Membrane ◽  
Membrane Bound ◽  
Morphological Identity ◽  
Non Equilibrium

Eukaryotic cells are characterized by having well defined internal membrane bound organelles with distinct morphological identity. We explore the issue of morphogenesis in the context of organelles subject to intense membrane trafficking and show that non-equilibrium driven processes are at the heart of organelle morphogenesis.

scholarly journals Atg27 Is Required for Autophagy-dependent Cycling of Atg9

2007 ◽  
Vol 18 (2) ◽  
pp. 581-593 ◽  
Author(s):  
Wei-Lien Yen ◽  
Julie E. Legakis ◽  
Usha Nair ◽  
Daniel J. Klionsky
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Golgi Complex ◽  
Transmembrane Protein ◽  
Eukaryotic Cells ◽  
Vesicle Formation ◽  
Catabolic Pathway ◽  
Autophagosome Formation ◽  
Yeast Saccharomyces Cerevisiae ◽  
Double Membrane ◽  
Selective Autophagy

Autophagy is a catabolic pathway for the degradation of cytosolic proteins or organelles and is conserved among all eukaryotic cells. The hallmark of autophagy is the formation of double-membrane cytosolic vesicles, termed autophagosomes, which sequester cytoplasm; however, the mechanism of vesicle formation and the membrane source remain unclear. In the yeast Saccharomyces cerevisiae, selective autophagy mediates the delivery of specific cargos to the vacuole, the analog of the mammalian lysosome. The transmembrane protein Atg9 cycles between the mitochondria and the pre-autophagosomal structure, which is the site of autophagosome biogenesis. Atg9 is thought to mediate the delivery of membrane to the forming autophagosome. Here, we characterize a second transmembrane protein Atg27 that is required for specific autophagy in yeast. Atg27 is required for Atg9 cycling and shuttles between the pre-autophagosomal structure, mitochondria, and the Golgi complex. These data support a hypothesis that multiple membrane sources supply the lipids needed for autophagosome formation.

scholarly journals Snapin associates with late endocytic compartments and interacts with late endosomal SNAREs

2009 ◽  
Vol 29 (4) ◽  
pp. 261-269 ◽  
Author(s):  
Li Lu ◽  
Qian Cai ◽  
Jin-Hua Tian ◽  
Zu-Hang Sheng
Keyword(s):  
Membrane Trafficking ◽  
Critical Role ◽  
Degradation Process ◽  
Late Endosome ◽  
Snare Proteins ◽  
Genetic Mouse Model ◽  
Protein Receptor ◽  
Important Regulator ◽  
Endocytic Compartments ◽  
Synaptic Vesicle Fusion

Late endocytic membrane trafficking delivers target materials and newly synthesized hydrolases into lysosomes and is critical for maintaining an efficient degradation process and cellular homoeostasis. Although some features of late endosome–lysosome trafficking have been described, the mechanisms underlying regulation of this event remain to be elucidated. Our previous studies showed that Snapin, as a SNAP25 (25 kDa synaptosome-associated protein)-binding protein, plays a critical role in priming synaptic vesicles for synchronized fusion in neurons. In the present study, we report that Snapin also associates with late endocytic membranous organelles and interacts with the late endosome-targeted SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) complex. Using a genetic mouse model, we further discovered that Snapin is required to maintain a proper balance of the late endocytic protein LAMP-1 (lysosome-associated membrane protein-1) and late endosomal SNARE proteins syntaxin 8 and Vti1b (vesicle transport through interaction with target SNAREs homologue 1b). Deleting the snapin gene in mice selectively led to the accumulation of these proteins in late endocytic organelles. Thus our present study suggests that Snapin serves as an important regulator of the late endocytic fusion machinery, in addition to its established role in regulating synaptic vesicle fusion.

scholarly journals Requirement of the N-Terminal Extension for Vacuolar Trafficking and Transport Activity of Yeast Ycf1p, an ATP-binding Cassette Transporter

2002 ◽  
Vol 13 (12) ◽  
pp. 4443-4455 ◽  
Author(s):  
Deborah L. Mason ◽  
Susan Michaelis
Keyword(s):  
Abc Transporters ◽  
Membrane Trafficking ◽  
Critical Role ◽  
Vacuolar Membrane ◽  
Transport Processes ◽  
Proteolytic Processing ◽  
Atp Binding ◽  
Cadmium Resistance ◽  
Dependent Transport ◽  
Atp Binding Cassette

Ycf1p is the prototypical member of the yeast multidrug resistance-associated protein (MRP) subfamily of ATP-binding cassette (ABC) transporters. Ycf1p resides in the vacuolar membrane and mediates glutathione-dependent transport processes that result in resistance to cadmium and other xenobiotics. A feature common to many MRP proteins that distinguishes them from other ABC transporters is the presence of a hydrophobic N-terminal extension (NTE), whose function is not clearly established. The NTE contains a membrane spanning domain (MSD0) with five transmembrane spans and a cytosolic linker region (L0). The goal of this study was to determine the functional significance of the NTE of Ycf1p by examining the localization and functional properties of Ycf1p partial molecules, expressed either singly or together. We show that MSD0 plays a critical role in the vacuolar membrane trafficking of Ycf1p, whereas L0 is dispensable for localization. On the other hand, L0 is required for transport function, as determined by monitoring cadmium resistance. We also examine an unusual aspect of Ycf1p biology, namely, the posttranslational proteolytic processing that occurs within a lumenal loop of Ycf1p. Processing is shown to be Pep4p dependent and thus serves as a convenient marker for proper vacuolar localization. The processed fragments associate with each other, suggesting that these natural cleavage products contribute together to Ycf1p function.

scholarly journals 4-phenylbutyrate restored GABA uptake and reduced seizures in SLC6A1 variants-mediated disorders

2021 ◽  
Author(s):  
Gerald I Nwosu ◽  
Felicia Mermer ◽  
Carson Flamm ◽  
Sarah Poliquin ◽  
Wangzhen Shen ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Membrane Trafficking ◽  
Protein Trafficking ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Gaba Uptake ◽  
Functional Protein ◽  
Great Opportunity ◽  
Treatment Development ◽  
The Impact

We have previously studied the molecular mechanisms of solute carrier family 6 member 1 (SLC6A1) associated with a continuum of neurodevelopmental disorders, including various epilepsy syndromes, autism, and intellectual disability. Based on functional assays of variants in a large cohort with heterogenous clinical phenotypes, we conclude that partial or complete loss of GABA uptake function in the mutant GAT-1 is the primary etiology as identified in GABAA receptor mutation-mediated epilepsy and in cystic fibrosis. Importantly, we identified that there are common patterns of the mutant protein trafficking from biogenesis, oligomerization, glycosylation, and translocation to the cell membrane across variants with the conservation of this process across cell types. Conversely any approach to facilitate membrane trafficking would increase presence of the functional protein in the targeted destination in all involved cells. PBA is an FDA-approved drug for pediatric use and is orally bioavailable so it can be quickly translated to patient use. It has been demonstrated that PBA can correct protein misfolding, reduce ER stress, and attenuate unfolded protein response in neurodegenerative diseases, it has also showed promise in treatment of cystic fibrosis. The common cellular mechanisms shared by the mutant GAT-1 and the mutant cystic fibrosis transmembrane conductance regulator led us to test if PBA and other pharmaco-chaperones could be a potential treatment option for SLC6A1 mutations. We examined the impact of PBA and other small molecules in a library of variants and in cell and knockin mouse models. Because of the critical role of astrocytic GAT-1 deficit in seizures, we focused on astrocytes, and demonstrated that the existence of the mutant GAT-1 retained the wildtype GAT-1, suggesting aberrant protein oligomerization and trafficking caused by the mutant GAT-1. PBA increased GABA uptake in both mouse and human astrocytes bearing the mutations. Importantly, PBA increased GAT-1 expression and suppressed spike wave discharges (SWDS) in the heterozygous knockin mice. Although the detailed mechanisms of action for PBA are ambiguous, it is likely that PBA can facilitate the forward trafficking of the wildtype GAT-1 favoring over the mutant GAT-1, thus increasing GABA uptake. Since all patients with SLC6A1 mutations are heterozygous and carry one wildtype functional allele, this suggests a great opportunity for treatment development by leveraging the endogenous protein trafficking pathway to promote forward trafficking of the wildtype in combination with enhancing the disposal of the mutant allele as treatment mode. The study opens a novel avenue of treatment development for genetic epilepsy via drug repurposing.

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