scholarly journals Lamp1 mediates lipid transport, but is dispensable for autophagy in Drosophila

2021 ◽  
Author(s):  
Norin Chaudhry ◽  
Margaux Sica ◽  
Satya Surabhi ◽  
David Sanchez Hernandez ◽  
Ana Mesquita ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Double Mutant ◽  
Energy State ◽  
Lipid Transport ◽  
Cholesterol Trafficking ◽  
Ideal Model ◽  
Lipid Species ◽  
Bona Fide ◽  
Acidic Compartment

AbstractThe endolysosomal system not only is an integral part of the cellular catabolic machinery that processes and recycles nutrients for synthesis of biomaterials, but also acts as signaling hub to sense and coordinate the energy state of cells with growth and differentiation. Lysosomal dysfunction adversely influences vesicular transport-dependent macromolecular degradation and thus causes serious problems for human health. In mammalian cells, loss of the lysosome associated membrane proteins LAMP1/2 strongly impacts autophagy and cholesterol trafficking. Here we show that the previously uncharacterized Drosophila Lamp1 is a bona fide homolog of vertebrate LAMP1/2. Surprisingly and in contrast to Lamp1/2 double mutant mice, Drosophila Lamp1 is not required for viability or autophagy, suggesting that autophagy defects in Lamp1/2 mutants may have indirect causes. However, Lamp1 deficiency results in an expansion of the acidic compartment in flies. Furthermore, we find that Lamp1 mutant larvae have defects in lipid metabolism as they show elevated levels of sterols and diacylglycerols (DAGs). Since DAGs are the main lipid species used for transport though the hemolymph (blood) in insects, our results indicate broader functions of Lamp1 in lipid transport. Our findings make Drosophila an ideal model to study the role of LAMP proteins in lipid assimilation without the confounding effects of their storage and without interfering with autophagic processes.

scholarly journals C4orf41 and TTC-15 are mammalian TRAPP components with a role at an early stage in ER-to-Golgi trafficking

2011 ◽  
Vol 22 (12) ◽  
pp. 2083-2093 ◽  
Author(s):  
P. James Scrivens ◽  
Baraa Noueihed ◽  
Nassim Shahrzad ◽  
Sokunthear Hul ◽  
Stephanie Brunet ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Multidisciplinary Approach ◽  
Early Stage ◽  
Binary Interaction ◽  
The Novel ◽  
Novel Proteins ◽  
Bona Fide ◽  
Interaction Map ◽  
Equivalent Complex

TRAPP is a multisubunit tethering complex implicated in multiple vesicle trafficking steps in Saccharomyces cerevisiae and conserved throughout eukarya, including humans. Here we confirm the role of TRAPPC2L as a stable component of mammalian TRAPP and report the identification of four novel components of the complex: C4orf41, TTC-15, KIAA1012, and Bet3L. Two of the components, KIAA1012 and Bet3L, are mammalian homologues of Trs85p and Bet3p, respectively. The remaining two novel TRAPP components, C4orf41 and TTC-15, have no homologues in S. cerevisiae. With this work, human homologues of all the S. cerevisiae TRAPP proteins, with the exception of the Saccharomycotina-specific subunit Trs65p, have now been reported. Through a multidisciplinary approach, we demonstrate that the novel proteins are bona fide components of human TRAPP and implicate C4orf41 and TTC-15 (which we call TRAPPC11 and TRAPPC12, respectively) in ER-to-Golgi trafficking at a very early stage. We further present a binary interaction map for all known mammalian TRAPP components and evidence that TRAPP oligomerizes. Our data are consistent with the absence of a TRAPP I–equivalent complex in mammalian cells, suggesting that the fundamental unit of mammalian TRAPP is distinct from that characterized in S. cerevisiae.

scholarly journals Hydrogen Sulfide Biochemistry and Interplay with Other Gaseous Mediators in Mammalian Physiology

2018 ◽  
Vol 2018 ◽  
pp. 1-31 ◽  
Author(s):  
Alessandro Giuffrè ◽  
João B. Vicente
Keyword(s):  
Hydrogen Sulfide ◽  
Mammalian Cells ◽  
Protein Targets ◽  
Metal Centers ◽  
Cellular Processes ◽  
Signaling Function ◽  
Enzymatic Systems ◽  
Bona Fide ◽  
Different Levels

Hydrogen sulfide (H2S) has emerged as a relevant signaling molecule in physiology, taking its seat as a bona fide gasotransmitter akin to nitric oxide (NO) and carbon monoxide (CO). After being merely regarded as a toxic poisonous molecule, it is now recognized that mammalian cells are equipped with sophisticated enzymatic systems for H2S production and breakdown. The signaling role of H2S is mainly related to its ability to modify different protein targets, particularly by promoting persulfidation of protein cysteine residues and by interacting with metal centers, mostly hemes. H2S has been shown to regulate a myriad of cellular processes with multiple physiological consequences. As such, dysfunctional H2S metabolism is increasingly implicated in different pathologies, from cardiovascular and neurodegenerative diseases to cancer. As a highly diffusible reactive species, the intra- and extracellular levels of H2S have to be kept under tight control and, accordingly, regulation of H2S metabolism occurs at different levels. Interestingly, even though H2S, NO, and CO have similar modes of action and parallel regulatory targets or precisely because of that, there is increasing evidence of a crosstalk between the three gasotransmitters. Herein are reviewed the biochemistry, metabolism, and signaling function of hydrogen sulfide, as well as its interplay with the other gasotransmitters, NO and CO.

scholarly journals Use of photoactivatable sphingolipid analogues to monitor lipid transport in mammalian cells

1997 ◽  
Vol 328 (2) ◽  
pp. 489-498 ◽  
Author(s):  
M. P. Mirjam ZEGERS ◽  
Jan Willem KOK ◽  
Dick HOEKSTRA
Keyword(s):  
Mammalian Cells ◽  
Elevated Temperatures ◽  
Brefeldin A ◽  
Labelling Pattern ◽  
Lipid Transport ◽  
Specific Subset ◽  
Specific Proteins ◽  
Sphingolipid Biosynthesis ◽  
Derivatives Of

Photoactivatable derivatives of ceramide, glucosylceramide (GlcCer) and sphingomyelin {3-(p-azido-m-[125I]iodophenyl)propionylceramide, 3-(p-azido-m-[125I]iodophenyl)propionyl-GlcCer and 3-(p-azido-m-[125I]iodophenyl)propionylsphingomyelin} were synthesized in an attempt to identify compartment-specific proteins involved in sphingolipid sorting or metabolism. In HT29 and BHK cells the ceramide analogue entered the cell by monomeric diffusion, as evidenced by the probe's efficient internalization at low temperature (4 °C). In contrast, the photoactivatable GlcCer was internalized only at elevated temperatures (37 °C), presumably reflecting an endocytic mechanism of uptake. The photoactivatable ceramide was mainly metabolized to the corresponding sphingomyelin analogue, but small amounts of GlcCer and galactosylceramide were also synthesized. The newly synthesized photoreactive sphingomyelin was subsequently transported to the cell surface, a process that was effectively inhibited by the presence of brefeldin A. The incubation of cells with photoactivatable analogues at 4 °C, followed by illumination, led to the association of sphingolipid with a specific subset of proteins. The protein labelling pattern of ceramide differed from that of glucosylceramide. A further shift in labelling pattern was apparent when the cells were incubated with the lipid analogues at 37 °C. Moreover, most of the proteins labelled by photoreactive sphingomyelin seemed to be detergent-insoluble, which is indicative of a location in sphingolipid-rich microdomains at the plasma membrane. The potential of applying photoactivatable sphingolipids to further define and identify the role of distinct proteins in sphingolipid biosynthesis, transport and sorting, is discussed.

Autophagy Modulators and Neuroinflammation

2020 ◽  
Vol 27 (6) ◽  
pp. 955-982 ◽  
Author(s):  
Kyoung Sang Cho ◽  
Jang Ho Lee ◽  
Jeiwon Cho ◽  
Guang-Ho Cha ◽  
Gyun Jee Song
Keyword(s):  
Neurodegenerative Disorders ◽  
Neurological Disorders ◽  
Mammalian Cells ◽  
Critical Role ◽  
Therapeutic Agents ◽  
Mechanisms Of Action ◽  
Scientific Interest ◽  
Therapeutic Tools ◽  
Underlying Mechanisms

Background: Neuroinflammation plays a critical role in the development and progression of various neurological disorders. Therefore, various studies have focused on the development of neuroinflammation inhibitors as potential therapeutic tools. Recently, the involvement of autophagy in the regulation of neuroinflammation has drawn substantial scientific interest, and a growing number of studies support the role of impaired autophagy in the pathogenesis of common neurodegenerative disorders. Objective: The purpose of this article is to review recent research on the role of autophagy in controlling neuroinflammation. We focus on studies employing both mammalian cells and animal models to evaluate the ability of different autophagic modulators to regulate neuroinflammation. Methods: We have mostly reviewed recent studies reporting anti-neuroinflammatory properties of autophagy. We also briefly discussed a few studies showing that autophagy modulators activate neuroinflammation in certain conditions. Results: Recent studies report neuroprotective as well as anti-neuroinflammatory effects of autophagic modulators. We discuss the possible underlying mechanisms of action of these drugs and their potential limitations as therapeutic agents against neurological disorders. Conclusion: Autophagy activators are promising compounds for the treatment of neurological disorders involving neuroinflammation.

scholarly journals Phosphorylation of GAPVD1 Is Regulated by the PER Complex and Linked to GAPVD1 Degradation

2021 ◽  
Vol 22 (7) ◽  
pp. 3787
Author(s):  
Hussam Ibrahim ◽  
Philipp Reus ◽  
Anna Katharina Mundorf ◽  
Anna-Lena Grothoff ◽  
Valerie Rudenko ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Transcriptional Repression ◽  
Small Gtpase ◽  
Main Role ◽  
Interacting Proteins ◽  
Casein Kinase 1 ◽  
Bona Fide ◽  
Kinetics Of

Repressor protein period (PER) complexes play a central role in the molecular oscillator mechanism of the mammalian circadian clock. While the main role of nuclear PER complexes is transcriptional repression, much less is known about the functions of cytoplasmic PER complexes. We found with a biochemical screen for PER2-interacting proteins that the small GTPase regulator GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1), which has been identified previously as a component of cytoplasmic PER complexes in mice, is also a bona fide component of human PER complexes. We show that in situ GAPVD1 is closely associated with casein kinase 1 delta (CSNK1D), a kinase that regulates PER2 levels through a phosphoswitch mechanism, and that CSNK1D regulates the phosphorylation of GAPVD1. Moreover, phosphorylation determines the kinetics of GAPVD1 degradation and is controlled by PER2 and a C-terminal autoinhibitory domain in CSNK1D, indicating that the regulation of GAPVD1 phosphorylation is a novel function of cytoplasmic PER complexes and might be part of the oscillator mechanism or an output function of the circadian clock.

scholarly journals Genetic Studies of mei-P26 Reveal a Link Between the Processes That Control Germ Cell Proliferation in Both Sexes and Those That Control Meiotic Exchange in Drosophila

Genetics ◽  
2000 ◽  
Vol 155 (4) ◽  
pp. 1757-1772 ◽  
Author(s):  
Scott L Page ◽  
Kim S McKim ◽  
Benjamin Deneen ◽  
Tajia L Van Hook ◽  
R Scott Hawley
Keyword(s):  
Meiotic Recombination ◽  
Double Mutant ◽  
P Element ◽  
Genetic Studies ◽  
Germline Differentiation ◽  
Males And Females ◽  
Bag Of Marbles ◽  
Differentiation And Proliferation

Abstract We present the cloning and characterization of mei-P26, a novel P-element-induced exchange-defective female meiotic mutant in Drosophila melanogaster. Meiotic exchange in females homozygous for mei-P261 is reduced in a polar fashion, such that distal chromosomal regions are the most severely affected. Additional alleles generated by duplication of the P element reveal that mei-P26 is also necessary for germline differentiation in both females and males. To further assess the role of mei-P26 in germline differentiation, we tested double mutant combinations of mei-P26 and bag-of-marbles (bam), a gene necessary for the control of germline differentiation and proliferation in both sexes. A null mutation at the bam locus was found to act as a dominant enhancer of mei-P26 in both males and females. Interestingly, meiotic exchange in mei-P261; bamΔ86/+ females is also severely decreased in comparison to mei-P261 homozygotes, indicating that bam affects the meiotic phenotype as well. These data suggest that the pathways controlling germline differentiation and meiotic exchange are related and that factors involved in the mitotic divisions of the germline may regulate meiotic recombination.

scholarly journals Insights in the Role of Lipids, Oxidative Stress and Inflammation in Rheumatoid Arthritis Unveiled by New Trends in Lipidomic Investigations

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 45
Author(s):  
Helena Beatriz Ferreira ◽  
Tânia Melo ◽  
Artur Paiva ◽  
Maria do Rosário Domingues
Keyword(s):  
Rheumatoid Arthritis ◽  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Lipid Profile ◽  
Inflammatory Responses ◽  
Molecular Level ◽  
Lipid Hydroperoxides ◽  
Lipid Species ◽  
Inflammatory Autoimmune Disease

Rheumatoid arthritis (RA) is a highly debilitating chronic inflammatory autoimmune disease most prevalent in women. The true etiology of this disease is complex, multifactorial, and is yet to be completely elucidated. However, oxidative stress and lipid peroxidation are associated with the development and pathogenesis of RA. In this case, oxidative damage biomarkers have been found to be significantly higher in RA patients, associated with the oxidation of biomolecules and the stimulation of inflammatory responses. Lipid peroxidation is one of the major consequences of oxidative stress, with the formation of deleterious lipid hydroperoxides and electrophilic reactive lipid species. Additionally, changes in the lipoprotein profile seem to be common in RA, contributing to cardiovascular diseases and a chronic inflammatory environment. Nevertheless, changes in the lipid profile at a molecular level in RA are still poorly understood. Therefore, the goal of this review was to gather all the information regarding lipid alterations in RA analyzed by mass spectrometry. Studies on the variation of lipid profile in RA using lipidomics showed that fatty acid and phospholipid metabolisms, especially in phosphatidylcholine and phosphatidylethanolamine, are affected in this disease. These promising results could lead to the discovery of new diagnostic lipid biomarkers for early diagnosis of RA and targets for personalized medicine.

A new functional role of mitochondria‐anchored protein ligase in peroxisome morphology in mammalian cells

2021 ◽  
Author(s):  
Abhishek Mohanty ◽  
Rodolfo Zunino ◽  
Vincent Soubannier ◽  
Shilpa Dilipkumar
Keyword(s):  
Mammalian Cells ◽  
Functional Role

scholarly journals The Population Genetics of Synthetic Lethals

Genetics ◽  
1998 ◽  
Vol 150 (1) ◽  
pp. 449-458 ◽  
Author(s):  
Patrick C Phillips ◽  
Norman A Johnson
Keyword(s):  
Double Mutant ◽  
Single Locus ◽  
Single Mutation ◽  
Hybrid Breakdown ◽  
Selection Coefficient ◽  
Deleterious Alleles ◽  
Synthetic Lethals ◽  
Mutant Homozygote ◽  
Diploid Model

Abstract Synthetic lethals are variants at different loci that have little or no effect on viability singly but cause lethality in combination. The importance of synthetic lethals and, more generally, of synthetic deleterious loci (SDL) has been controversial. Here, we derive the expected frequencies for SDL under a mutation-selection balance for the complete haploid model and selected cases of the diploid model. We have also obtained simple approximations that demonstrate good fit to exact solutions based on numerical iterations. In the haploid case, equilibrium frequencies of carrier haplotypes (individuals with only a single mutation) are comparable to analogous single-locus results, after allowing for the effects of linkage. Frequencies in the diploid case, however, are much higher and more comparable to the square root of the single-locus results. In particular, when selection operates only on the double-mutant homozygote and linkage is not too tight, the expected frequency of the carriers is approximately the quartic root of the ratio between the mutation rate and the selection coefficient of the synthetics. For a reasonably wide set of models, the frequencies of carriers can be on the order of a few percent. The equilibrium frequencies of these deleterious alleles can be relatively high because, with SDL, both dominance and epistasis act to shield carriers from exposure to selection. We also discuss the possible role of SDL in maintaining genetic variation and in hybrid breakdown.

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