scholarly journals Elevating PI3P drives select downstream membrane trafficking pathways

2020 ◽  
pp. mbc.E20-03-0191
Author(s):  
Noah Steinfeld ◽  
Vikramjit Lahiri ◽  
Anna Morrison ◽  
Shree Padma Metur ◽  
Daniel J. Klionsky ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Retrograde Transport ◽  
Lipid Kinase ◽  
Phosphoinositide Signaling ◽  
Cellular Processes ◽  
Vacuole Fusion ◽  
General Defect ◽  
Downstream Processes ◽  
The Impact ◽  
Phosphatidylinositol 3

Phosphoinositide signaling lipids are essential for several cellular processes. The requirement for a phosphoinositide is conventionally studied by depleting the corresponding lipid kinase. However, there are very few reports on the impact of elevating phosphoinositides. That phosphoinositides are dynamically elevated in response to stimuli suggests that, in addition to being required, phosphoinositides drive downstream pathways. To test this hypothesis, we elevated the levels of phosphatidylinositol-3-phosphate (PI3P) by generating hyperactive alleles of the yeast phosphatidylinositol 3-kinase, Vps34. We find that hyperactive Vps34 drives certain pathways, including PI(3,5)P2 synthesis and retrograde transport from the vacuole. This demonstrates that PI3P is rate limiting in some pathways. Interestingly, hyperactive Vps34 does not affect ESCRT function. Thus, elevating PI3P does not always increase the rate of PI3P-dependent pathways. Elevating PI3P can also delay a pathway. Elevating PI3P slowed late steps in autophagy, in part by delaying the disassembly of autophagy proteins from mature autophagosomes as well as delaying fusion of autophagosomes with the vacuole. This latter defect is likely due to a more general defect in vacuole fusion, as assessed by changes in vacuole morphology. These studies suggest that stimulus-induced elevation of phosphoinositides provides a way for these stimuli to selectively regulate downstream processes.

scholarly journals Characterization of the Regulation and Function of Phosphatidylinositol 3,5-Bisphosphate

2021 ◽  
Author(s):  
Shannon Cheuk Ying Ho
Keyword(s):  
Membrane Trafficking ◽  
Adaptor Protein ◽  
Cellular Functions ◽  
Lipid Kinase ◽  
Cellular Processes ◽  
Lipid Phosphatase ◽  
Tooth Type ◽  
And Function ◽  
Endocytic Compartments ◽  
Lysosomal Acidification

PtdIns(3,5)P2 is a low abundance phosphoinositide that is involved in a variety of cellular processes. Most notably, PtdIns(3,5)P2 is known to regulate vacuolar/lysosomal morphology. Deficiency in PtdIns(3,5)P2 results in enlargement of the yeast vacuole and, an extensive vacuolation of the late endocytic compartments in higher eukaryotes (1, 2). In addition, PtdIns(3,5)P2 is also involved in cellular functions including membrane trafficking, autophagy, and vacuolar/lysosomal acidification. However, the current study provided evidence that shows that the vacuole/lysosomes of PtdIns(3,5)P2-deficient cells remain acidic. Hence, PtdIns(3,5)P2 may not have a role in steady-state vacuolar/lysosomal acidification. PtdIns(3,5)P2 is synthesized by the Fab1 lipid kinase and degraded by the antagonistic Fig4 lipid phosphatase. Vac14, an adaptor protein, is known to interact with both Fab1 and Fig4 to form a complex on the vacuolar membrane. This study demonstrated that Vac14 is required to form a homodimer for its interaction with Fig4 and Fab1. In addition, formation of the homodimer is necessary for regulation of PtdIns(3,5)P2. Mutations in human Vac14 and Fig4 has been identified in patients with neurodegenerative diseases, such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth Type 4J (3, 4). This study provides an important stepping stone in characterizing the regulatory mechanism and understanding the function of PtdIns(3,5)P2

scholarly journals Characterization of the Regulation and Function of Phosphatidylinositol 3,5-Bisphosphate

2021 ◽  
Author(s):  
Shannon Cheuk Ying Ho
Keyword(s):  
Membrane Trafficking ◽  
Adaptor Protein ◽  
Cellular Functions ◽  
Lipid Kinase ◽  
Cellular Processes ◽  
Lipid Phosphatase ◽  
Tooth Type ◽  
And Function ◽  
Endocytic Compartments ◽  
Lysosomal Acidification

PtdIns(3,5)P2 is a low abundance phosphoinositide that is involved in a variety of cellular processes. Most notably, PtdIns(3,5)P2 is known to regulate vacuolar/lysosomal morphology. Deficiency in PtdIns(3,5)P2 results in enlargement of the yeast vacuole and, an extensive vacuolation of the late endocytic compartments in higher eukaryotes (1, 2). In addition, PtdIns(3,5)P2 is also involved in cellular functions including membrane trafficking, autophagy, and vacuolar/lysosomal acidification. However, the current study provided evidence that shows that the vacuole/lysosomes of PtdIns(3,5)P2-deficient cells remain acidic. Hence, PtdIns(3,5)P2 may not have a role in steady-state vacuolar/lysosomal acidification. PtdIns(3,5)P2 is synthesized by the Fab1 lipid kinase and degraded by the antagonistic Fig4 lipid phosphatase. Vac14, an adaptor protein, is known to interact with both Fab1 and Fig4 to form a complex on the vacuolar membrane. This study demonstrated that Vac14 is required to form a homodimer for its interaction with Fig4 and Fab1. In addition, formation of the homodimer is necessary for regulation of PtdIns(3,5)P2. Mutations in human Vac14 and Fig4 has been identified in patients with neurodegenerative diseases, such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth Type 4J (3, 4). This study provides an important stepping stone in characterizing the regulatory mechanism and understanding the function of PtdIns(3,5)P2

scholarly journals Characterizing the VAC14 multimeric state

2021 ◽  
Author(s):  
Shannon Cheuk Ying Ho
Keyword(s):  
Nervous System ◽  
Membrane Trafficking ◽  
Adaptor Protein ◽  
Lipid Kinase ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Cellular Processes ◽  
Lipid Phosphatase ◽  
Lateral Sclerosis ◽  
Tooth Disease

PtdIns(3,5)₂ is involved in a number of cellular processes, such as the regulation of endolysosome morphology and membrane trafficking, autophagy and ion transport. In mammala, PtdIns(3,5)₂ deficiency results in vacuolation most notable in the neurons of the central and peripheral nervous system. This can potentially block the trafficking of neurotransmitters leading to a progression of neurodegeneration diseases such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. PtdIns(3,5)₂ is synthesized by the Fab1/PIKfyve lipid kinase and degraded by the Fig4/Sac3 lipid phosphatase. Fab1 and Fig4 are found in a complex with its regulator, the Fac14/ArPIKfyve adaptor protein. The aim of this study was to identify the multimeric state of recombinant Vac14 in order to help elucidate the importance of the Vac14 multimer in the regulation of PtdIns(3,5)₂. The result of this study indicated that recombinant Vac14 forms a homodimer and/or homotrimer.

scholarly journals Characterizing the VAC14 multimeric state

2021 ◽  
Author(s):  
Shannon Cheuk Ying Ho
Keyword(s):  
Nervous System ◽  
Membrane Trafficking ◽  
Adaptor Protein ◽  
Lipid Kinase ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Cellular Processes ◽  
Lipid Phosphatase ◽  
Lateral Sclerosis ◽  
Tooth Disease

PtdIns(3,5)₂ is involved in a number of cellular processes, such as the regulation of endolysosome morphology and membrane trafficking, autophagy and ion transport. In mammala, PtdIns(3,5)₂ deficiency results in vacuolation most notable in the neurons of the central and peripheral nervous system. This can potentially block the trafficking of neurotransmitters leading to a progression of neurodegeneration diseases such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. PtdIns(3,5)₂ is synthesized by the Fab1/PIKfyve lipid kinase and degraded by the Fig4/Sac3 lipid phosphatase. Fab1 and Fig4 are found in a complex with its regulator, the Fac14/ArPIKfyve adaptor protein. The aim of this study was to identify the multimeric state of recombinant Vac14 in order to help elucidate the importance of the Vac14 multimer in the regulation of PtdIns(3,5)₂. The result of this study indicated that recombinant Vac14 forms a homodimer and/or homotrimer.

scholarly journals Arginine Decarboxylase Is Essential for Pneumococcal Stress Responses

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 286
Author(s):  
Mary Frances Nakamya ◽  
Moses B. Ayoola ◽  
Leslie A. Shack ◽  
Mirghani Mohamed ◽  
Edwin Swiatlo ◽  
...  
Keyword(s):  
Stress Responses ◽  
Critical Role ◽  
Acid Stress ◽  
Arginine Decarboxylase ◽  
Arginine Deiminase ◽  
Dependent Manner ◽  
Cellular Processes ◽  
Opportunistic Human Pathogen ◽  
Thiol Peroxidase ◽  
The Impact

Polyamines such as putrescine, cadaverine, and spermidine are small cationic molecules that play significant roles in cellular processes, including bacterial stress responses and host–pathogen interactions. Streptococcus pneumoniae is an opportunistic human pathogen, which causes several diseases that account for significant morbidity and mortality worldwide. As it transits through different host niches, S. pneumoniae is exposed to and must adapt to different types of stress in the host microenvironment. We earlier reported that S. pneumoniae TIGR4, which harbors an isogenic deletion of an arginine decarboxylase (ΔspeA), an enzyme that catalyzes the synthesis of agmatine in the polyamine synthesis pathway, has a reduced capsule. Here, we report the impact of arginine decarboxylase deletion on pneumococcal stress responses. Our results show that ΔspeA is more susceptible to oxidative, nitrosative, and acid stress compared to the wild-type strain. Gene expression analysis by qRT-PCR indicates that thiol peroxidase, a scavenger of reactive oxygen species and aguA from the arginine deiminase system, could be important for peroxide stress responses in a polyamine-dependent manner. Our results also show that speA is essential for endogenous hydrogen peroxide and glutathione production in S. pneumoniae. Taken together, our findings demonstrate the critical role of arginine decarboxylase in pneumococcal stress responses that could impact adaptation and survival in the host.

scholarly journals Modulation of Endosome Function, Vesicle Trafficking and Autophagy by Human Herpesviruses

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 542
Author(s):  
Eduardo I. Tognarelli ◽  
Antonia Reyes ◽  
Nicolás Corrales ◽  
Leandro J. Carreño ◽  
Susan M. Bueno ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Viral Gene ◽  
Barr Virus ◽  
Cellular Processes ◽  
Antiviral Therapies ◽  
Host Determinants ◽  
Viral Particles ◽  
Life Threatening ◽  
Epstein Barr ◽  
Human Herpesviruses

Human herpesviruses are a ubiquitous family of viruses that infect individuals of all ages and are present at a high prevalence worldwide. Herpesviruses are responsible for a broad spectrum of diseases, ranging from skin and mucosal lesions to blindness and life-threatening encephalitis, and some of them, such as Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein–Barr virus (EBV), are known to be oncogenic. Furthermore, recent studies suggest that some herpesviruses may be associated with developing neurodegenerative diseases. These viruses can establish lifelong infections in the host and remain in a latent state with periodic reactivations. To achieve infection and yield new infectious viral particles, these viruses require and interact with molecular host determinants for supporting their replication and spread. Important sets of cellular factors involved in the lifecycle of herpesviruses are those participating in intracellular membrane trafficking pathways, as well as autophagic-based organelle recycling processes. These cellular processes are required by these viruses for cell entry and exit steps. Here, we review and discuss recent findings related to how herpesviruses exploit vesicular trafficking and autophagy components by using both host and viral gene products to promote the import and export of infectious viral particles from and to the extracellular environment. Understanding how herpesviruses modulate autophagy, endolysosomal and secretory pathways, as well as other prominent trafficking vesicles within the cell, could enable the engineering of novel antiviral therapies to treat these viruses and counteract their negative health effects.

scholarly journals Roles of Microglial Ion Channel in Neurodegenerative Diseases

2021 ◽  
Vol 10 (6) ◽  
pp. 1239
Author(s):  
Alexandru Cojocaru ◽  
Emilia Burada ◽  
Adrian-Tudor Bălșeanu ◽  
Alexandru-Florian Deftu ◽  
Bogdan Cătălin ◽  
...  
Keyword(s):  
Ion Channels ◽  
Neurodegenerative Diseases ◽  
Excitable Cells ◽  
Proton Channels ◽  
Voltage Gated ◽  
Cellular Processes ◽  
Pathological Conditions ◽  
The Common ◽  
Transient Receptor ◽  
The Impact

As the average age and life expectancy increases, the incidence of both acute and chronic central nervous system (CNS) pathologies will increase. Understanding mechanisms underlying neuroinflammation as the common feature of any neurodegenerative pathology, we can exploit the pharmacology of cell specific ion channels to improve the outcome of many CNS diseases. As the main cellular player of neuroinflammation, microglia play a central role in this process. Although microglia are considered non-excitable cells, they express a variety of ion channels under both physiological and pathological conditions that seem to be involved in a plethora of cellular processes. Here, we discuss the impact of modulating microglia voltage-gated, potential transient receptor, chloride and proton channels on microglial proliferation, migration, and phagocytosis in neurodegenerative diseases.

scholarly journals Impact of Environmental Stressors on Gene Expression in the Embryo of the Italian Wall Lizard

2021 ◽  
Vol 11 (11) ◽  
pp. 4723
Author(s):  
Rosaria Scudiero ◽  
Chiara Maria Motta ◽  
Palma Simoniello
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Membrane Trafficking ◽  
Translational Regulation ◽  
Cellular Protection ◽  
Terrestrial Vertebrate ◽  
Expression Of Genes ◽  
Stress Changes ◽  
Probable Consequence ◽  
The Impact

The cleidoic eggs of oviparous reptiles are protected from the external environment by membranes and a parchment shell permeable to water and dissolved molecules. As a consequence, not only physical but also chemical insults can reach the developing embryos, interfering with gene expression. This review provides information on the impact of the exposure to cadmium contamination or thermal stress on gene expression during the development of Italian wall lizards of the genus Podarcis. The results obtained by transcriptomic analysis, although not exhaustive, allowed to identify some stress-reactive genes and, consequently, the molecular pathways in which these genes are involved. Cadmium-responsive genes encode proteins involved in cellular protection, metabolism and proliferation, membrane trafficking, protein interactions, neuronal transmission and plasticity, immune response, and transcription regulatory factors. Cold stress changes the expression of genes involved in transcriptional/translational regulation and chromatin remodeling and inhibits the transcription of a histone methyltransferase with the probable consequence of modifying the epigenetic control of DNA. These findings provide transcriptome-level evidence of how terrestrial vertebrate embryos cope with stress, giving a key to use in population survival and environmental change studies. A better understanding of the genes contributing to stress tolerance in vertebrates would facilitate methodologies and applications aimed at improving resistance to unfavourable environments.

scholarly journals Interphotoreceptor coupling: an evolutionary perspective

2021 ◽  
Author(s):  
Lorenzo Cangiano ◽  
Sabrina Asteriti
Keyword(s):  
Visual Information ◽  
Signal To Noise Ratio ◽  
Electrical Coupling ◽  
Physiological Role ◽  
Cellular Processes ◽  
Contact Points ◽  
Highly Sensitive ◽  
The Many ◽  
The Impact

AbstractIn the vertebrate retina, signals generated by cones of different spectral preference and by highly sensitive rod photoreceptors interact at various levels to extract salient visual information. The first opportunity for such interaction is offered by electrical coupling of the photoreceptors themselves, which is mediated by gap junctions located at the contact points of specialised cellular processes: synaptic terminals, telodendria and radial fins. Here, we examine the evolutionary pressures for and against interphotoreceptor coupling, which are likely to have shaped how coupling is deployed in different species. The impact of coupling on signal to noise ratio, spatial acuity, contrast sensitivity, absolute and increment threshold, retinal signal flow and colour discrimination is discussed while emphasising available data from a variety of vertebrate models spanning from lampreys to primates. We highlight the many gaps in our knowledge, persisting discrepancies in the literature, as well as some major unanswered questions on the actual extent and physiological role of cone-cone, rod-cone and rod-rod communication. Lastly, we point toward limited but intriguing evidence suggestive of the ancestral form of coupling among ciliary photoreceptors.

scholarly journals Structural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shirley Tremel ◽  
Yohei Ohashi ◽  
Dustin R. Morado ◽  
Jessie Bertram ◽  
Olga Perisic ◽  
...  
Keyword(s):  
Complex I ◽  
Kinase Domain ◽  
Beclin 1 ◽  
Structural Basis ◽  
Rab Gtpases ◽  
Lipid Kinase ◽  
Complex Ii ◽  
Cellular Processes ◽  
Specific Complex ◽  
Electron Cryotomography

AbstractThe lipid phosphatidylinositol-3-phosphate (PI3P) is a regulator of two fundamental but distinct cellular processes, endocytosis and autophagy, so its generation needs to be under precise temporal and spatial control. PI3P is generated by two complexes that both contain the lipid kinase VPS34: complex II on endosomes (VPS34/VPS15/Beclin 1/UVRAG), and complex I on autophagosomes (VPS34/VPS15/Beclin 1/ATG14L). The endosomal GTPase Rab5 binds complex II, but the mechanism of VPS34 activation by Rab5 has remained elusive, and no GTPase is known to bind complex I. Here we show that Rab5a–GTP recruits endocytic complex II to membranes and activates it by binding between the VPS34 C2 and VPS15 WD40 domains. Electron cryotomography of complex II on Rab5a-decorated vesicles shows that the VPS34 kinase domain is released from inhibition by VPS15 and hovers over the lipid bilayer, poised for catalysis. We also show that the GTPase Rab1a, which is known to be involved in autophagy, recruits and activates the autophagy-specific complex I, but not complex II. Both Rabs bind to the same VPS34 interface but in a manner unique for each. These findings reveal how VPS34 complexes are activated on membranes by specific Rab GTPases and how they are recruited to unique cellular locations.

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