scholarly journals Microtubules are necessary for proper Reticulon localization during mitosis

2019 ◽  
Author(s):  
Zane J. Bergman ◽  
Ulises Diaz ◽  
Amanda Sims ◽  
Blake Riggs
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Disorders ◽  
Early Embryo ◽  
Drosophila Embryo ◽  
Microtubule Cytoskeleton ◽  
Spindle Poles ◽  
And Function ◽  
Insight Into

AbstractDuring mitosis, the structure of the Endoplasmic Reticulum (ER) displays a dramatic reorganization and remodeling event, however the mechanism driving these changes is poorly understood. Recently, the Reticulon family of ER shaping proteins has been identified as possible factors to promote these drastic changes in ER morphology. In addition, the Reticulons and other ER shaping proteins have been directly linked to several hereditary neurodegenerative disorders. Here, we provide key insight into the cytoskeletal factors involved in the Drosophila Reticulon, Reticulon-like 1 (Rtnl1) during mitosis in the early embryo. At prometaphase, Rtnl1 localizes at the spindle poles just prior to the bulk of ER localization suggesting a role in recruitment. Using precise temporal injections of cytoskeletal inhibitors in the early syncytial Drosophila embryo, we show that microtubules, not microfilaments are necessary for proper Rtnl1 localization and function during mitosis. Lastly, we show that astral microtubules are necessary for Rtnl1 localization at the spindle poles early in mitosis. This work highlights the role of the microtubule cytoskeleton in Rtnl1 localization and ER dynamics during mitosis and sheds light on a pathway towards inheritance of this major organelle.

scholarly journals Structural Insight into the Mechanism of N-Linked Glycosylation by Oligosaccharyltransferase

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 624 ◽  
Author(s):  
Smita Mohanty ◽  
Bharat P Chaudhary ◽  
David Zoetewey
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Modification ◽  
Cell Communication ◽  
Reticulum Cell ◽  
Enzyme Complex ◽  
Single Polypeptide Chain ◽  
Domains Of Life ◽  
And Function ◽  
Insight Into

Asparagine-linked glycosylation, also known as N-linked glycosylation is an essential and highly conserved post-translational protein modification that occurs in all three domains of life. This modification is essential for specific molecular recognition, protein folding, sorting in the endoplasmic reticulum, cell–cell communication, and stability. Defects in N-linked glycosylation results in a class of inherited diseases known as congenital disorders of glycosylation (CDG). N-linked glycosylation occurs in the endoplasmic reticulum (ER) lumen by a membrane associated enzyme complex called the oligosaccharyltransferase (OST). In the central step of this reaction, an oligosaccharide group is transferred from a lipid-linked dolichol pyrophosphate donor to the acceptor substrate, the side chain of a specific asparagine residue of a newly synthesized protein. The prokaryotic OST enzyme consists of a single polypeptide chain, also known as single subunit OST or ssOST. In contrast, the eukaryotic OST is a complex of multiple non-identical subunits. In this review, we will discuss the biochemical and structural characterization of the prokaryotic, yeast, and mammalian OST enzymes. This review explains the most recent high-resolution structures of OST determined thus far and the mechanistic implication of N-linked glycosylation throughout all domains of life. It has been shown that the ssOST enzyme, AglB protein of the archaeon Archaeoglobus fulgidus, and the PglB protein of the bacterium Campylobactor lari are structurally and functionally similar to the catalytic Stt3 subunit of the eukaryotic OST enzyme complex. Yeast OST enzyme complex contains a single Stt3 subunit, whereas the human OST complex is formed with either STT3A or STT3B, two paralogues of Stt3. Both human OST complexes, OST-A (with STT3A) and OST-B (containing STT3B), are involved in the N-linked glycosylation of proteins in the ER. The cryo-EM structures of both human OST-A and OST-B complexes were reported recently. An acceptor peptide and a donor substrate (dolichylphosphate) were observed to be bound to the OST-B complex whereas only dolichylphosphate was bound to the OST-A complex suggesting disparate affinities of two OST complexes for the acceptor substrates. However, we still lack an understanding of the independent role of each eukaryotic OST subunit in N-linked glycosylation or in the stabilization of the enzyme complex. Discerning the role of each subunit through structure and function studies will potentially reveal the mechanistic details of N-linked glycosylation in higher organisms. Thus, getting an insight into the requirement of multiple non-identical subunits in the N-linked glycosylation process in eukaryotes poses an important future goal.

Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor Edar

Development ◽  
2002 ◽  
Vol 129 (10) ◽  
pp. 2541-2553 ◽  
Author(s):  
Johanna Laurikkala ◽  
Johanna Pispa ◽  
Han-Sung Jung ◽  
Pekka Nieminen ◽  
Marja Mikkola ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Hair Follicles ◽  
Wild Type ◽  
Mutant Mouse Embryos ◽  
Anhidrotic Ectodermal Dysplasia ◽  
Embryonic Morphogenesis ◽  
Hair Follicle Development ◽  
And Function ◽  
Insight Into

X-linked and autosomal forms of anhidrotic ectodermal dysplasia syndromes (HED) are characterized by deficient development of several ectodermal organs, including hair, teeth and exocrine glands. The recent cloning of the genes that underlie these syndromes, ectodysplasin (ED1) and the ectodysplasin A receptor (EDAR), and their identification as a novel TNF ligand-receptor pair suggested a role for TNF signaling in embryonic morphogenesis. In the mouse, the genes of the spontaneous mutations Tabby (Ta) and downless (dl) were identified as homologs of ED1 and EDAR, respectively. To gain insight into the function of this signaling pathway in development of skin and hair follicles, we analyzed the expression and regulation of Eda and Edar in wild type as well as Tabby and Lef1 mutant mouse embryos. We show that Eda and Edar expression is confined to the ectoderm and occurs in a pattern that suggests a role of ectodysplasin/Edar signaling in the interactions between the ectodermal compartments and the formation and function of hair placodes. By using skin explant cultures, we further show that this signaling pathway is intimately associated with interactions between the epithelial and mesenchymal tissues. We also find that Ta mutants lack completely the placodes of the first developing tylotrich hairs, and that they do not show patterned expression of placodal genes, including Bmp4, Lef1, Shh, Ptch and Edar, and the genes for β-catenin and activin A. Finally, we identified activin as a mesenchymal signal that stimulates Edar expression and WNT as a signal that induces Eda expression, suggesting a hierarchy of distinct signaling pathways in the development of skin and hair follicles. In conclusion, we suggest that Eda and Edar are associated with the onset of ectodermal patterning and that ectodysplasin/edar signaling also regulates the morphogenesis of hair follicles.

scholarly journals Role of Biological Sex in the Cardiovascular-Gut Microbiome Axis

2022 ◽  
Vol 8 ◽  
Author(s):  
Shuangyue Li ◽  
Georgios Kararigas
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Microbial Composition ◽  
Biological Sex ◽  
Technological Advances ◽  
Host Health ◽  
Health And Disease ◽  
And Function ◽  
Insight Into

There has been a recent, unprecedented interest in the role of gut microbiota in host health and disease. Technological advances have dramatically expanded our knowledge of the gut microbiome. Increasing evidence has indicated a strong link between gut microbiota and the development of cardiovascular diseases (CVD). In the present article, we discuss the contribution of gut microbiota in the development and progression of CVD. We further discuss how the gut microbiome may differ between the sexes and how it may be influenced by sex hormones. We put forward that regulation of microbial composition and function by sex might lead to sex-biased disease susceptibility, thereby offering a mechanistic insight into sex differences in CVD. A better understanding of this could identify novel targets, ultimately contributing to the development of innovative preventive, diagnostic and therapeutic strategies for men and women.

Emergence of the Unmarked in Indian Englishes with Different Substrates

2014 ◽  
Author(s):  
Caroline R. Wiltshire
Keyword(s):  
Second Language ◽  
Second Language Acquisition ◽  
Optimality Theory ◽  
Learning Algorithm ◽  
Indian English ◽  
Form And Function ◽  
First Languages ◽  
And Function ◽  
Insight Into

This study uses data from Indian English as a second language, spoken by speakers of five first languages, to illustrate and evaluate the role of the emergence of the unmarked (TETU) in phonological theory. The analysis focusses on word-final consonant devoicing and cluster reduction, for which the five Indian first languages have various constraints, while Indian English is relatively unrestricted. Variation in L2 Indian Englishes results from both transfer of L1 phonotactics and the emergence of the unmarked, accounted for within Optimality Theory. The use of a learning algorithm also allows us to test the relative importance of markedness and frequency and to evaluate the relative markedness of various clusters. Thus, data from Indian Englishes provides insight into the form and function of markedness constraints, as well as the mechanisms of Second Language Acquisition (SLA).

scholarly journals Identification the role of mono-ADP-ribosylation in colorectal cancer by integrated Transcriptome analysis

2021 ◽  
Author(s):  
Shuxian Zhang ◽  
Jiale Duan ◽  
Yanping Yang ◽  
Hanjuan Gong ◽  
Yi Tang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endoplasmic Reticulum ◽  
Alternative Splicing ◽  
Enrichment Analysis ◽  
Drug Candidate ◽  
Post Translational Modification ◽  
Lentiviral Infection ◽  
Whole Transcriptome Sequencing ◽  
And Function

Abstract Purpose Our previous study has clarified the carcinogenic properties of arginine-specific mono-ADP ribosyltransferase 1(ART1), which is considered to be a critical post-translational modification that changes the structure and function of proteins and is widely involved in important processes. This study provides, for the first time, a comprehensive insight of transcriptomic analysis for colorectal cancer cells interfered with ART1 silencing by Illumina RNA-Seq and related verification experiments. Methods Lentiviral infection was used to construct a CT-26 cell line that stably knocks down the ART1 gene, a whole transcriptome sequencing technique was performed to identify differentially expressed genes (DEGs). GO and KEGG classification/enrichment analysis and verification experiments were performed to determine the role of ART1 in the progression of colorectal cancer. Results a total of 5552 DEGs, GO function and KEGG pathway with highest enrichment, forms of SNP and diverse splicing patterns were able to be identified. Importantly, knockdown of ART1 affected the occurrence of the splicing of certain key genes related to tumor cell growth, also down-regulated expression of the key gene PTBP1 for alternative splicing. The overall attenuation of the endoplasmic reticulum unfolded protein response (UPR) signaling pathway caused by ART1 inhibition would unbalance UPR signaling, leading to the occurrence of apoptosis to impede tumorigenesis. Conclusion ART1, which clustered in organelles, may promote the development of colorectal cancer by participating in a variety of new mechanisms including endoplasmic reticulum stress regulation, metabolic process or alternative splicing, which may provide a good clinical drug candidate closer to targeted therapy of CRC.

scholarly journals A nanobody-based molecular toolkit provides new mechanistic insight into clathrin-coat initiation

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Linton M Traub
Keyword(s):  
Decisive Role ◽  
Subcellular Location ◽  
Combined Approach ◽  
Mechanistic Insight ◽  
Early Endosomes ◽  
The Stability ◽  
And Function ◽  
Insight Into ◽  
Complementarity Determining Region

Besides AP-2 and clathrin triskelia, clathrin coat inception depends on a group of early-arriving proteins including Fcho1/2 and Eps15/R. Using genome-edited cells, we described the role of the unstructured Fcho linker in stable AP-2 membrane deposition. Here, expanding this strategy in combination with a new set of llama nanobodies against EPS15 shows an FCHO1/2–EPS15/R partnership plays a decisive role in coat initiation. A nanobody containing an Asn-Pro-Phe peptide within the complementarity-determining region 3 loop is a function-blocking pseudoligand for tandem EPS15/R EH domains. Yet, in living cells, EH domains gathered at clathrin-coated structures are poorly accessible, indicating residence by endogenous NPF-bearing partners. Forcibly sequestering cytosolic EPS15 in genome-edited cells with nanobodies tethered to early endosomes or mitochondria changes the subcellular location and availability of EPS15. This combined approach has strong effects on clathrin coat structure and function by dictating the stability of AP-2 assemblies at the plasma membrane.

scholarly journals Novel Insight Into the Development and Function of Hypopharyngeal Glands in Honey Bees

2021 ◽  
Vol 11 ◽  
Author(s):  
Saboor Ahmad ◽  
Shahmshad Ahmed Khan ◽  
Khalid Ali Khan ◽  
Jianke Li
Keyword(s):  
Honey Bees ◽  
Future Research ◽  
Factors Affecting ◽  
Hypopharyngeal Glands ◽  
And Function ◽  
First Time ◽  
The Brain ◽  
Insight Into ◽  
Made In

Hypopharyngeal glands (HGs) are the most important organ of hymenopterans which play critical roles for the insect physiology. In honey bees, HGs are paired structures located bilaterally in the head, in front of the brain between compound eyes. Each gland is composed of thousands of secretory units connecting to secretory duct in worker bees. To better understand the recent progress made in understanding the structure and function of these glands, we here review the ontogeny of HGs, and the factors affecting the morphology, physiology, and molecular basis of the functionality of the glands. We also review the morphogenesis of HGs in the pupal and adult stages, and the secretory role of the glands across the ages for the first time. Furthermore, recent transcriptome, proteome, and phosphoproteome analyses have elucidated the potential mechanisms driving the HGs development and functionality. This adds a comprehensive novel knowledge of the development and physiology of HGs in honey bees over time, which may be helpful for future research investigations.

scholarly journals C-terminus of the P4-ATPase ATP8A2 functions in protein folding and regulation of phospholipid flippase activity

2017 ◽  
Vol 28 (3) ◽  
pp. 452-462 ◽  
Author(s):  
Madhavan Chalat ◽  
Kody Moleschi ◽  
Robert S. Molday
Keyword(s):  
Endoplasmic Reticulum ◽  
Atpase Activity ◽  
Deletion Mutants ◽  
Serine Residue ◽  
Cellular Processes ◽  
Phospholipid Asymmetry ◽  
C Terminus ◽  
And Function ◽  
Phospholipid Flippase

ATP8A2 is a P4-ATPase that flips phosphatidylserine and phosphatidylethanolamine across cell membranes. This generates membrane phospholipid asymmetry, a property important in many cellular processes, including vesicle trafficking. ATP8A2 deficiency causes severe neurodegenerative diseases. We investigated the role of the C-terminus of ATP8A2 in its expression, subcellular localization, interaction with its subunit CDC50A, and function as a phosphatidylserine flippase. C-terminal deletion mutants exhibited a reduced tendency to solubilize in mild detergent and exit the endoplasmic reticulum. The solubilized protein, however, assembled with CDC50A and displayed phosphatidylserine flippase activity. Deletion of the C-terminal 33 residues resulted in reduced phosphatidylserine-dependent ATPase activity, phosphatidylserine flippase activity, and neurite extension in PC12 cells. These reduced activities were reversed with 60- and 80-residue C-terminal deletions. Unlike the yeast P4-ATPase Drs2, ATP8A2 is not regulated by phosphoinositides but undergoes phosphorylation on the serine residue within a CaMKII target motif. We propose a model in which the C-terminus of ATP8A2 consists of an autoinhibitor domain upstream of the C-terminal 33 residues and an anti-autoinhibitor domain at the extreme C-terminus. The latter blocks the inhibitory activity of the autoinhibitor domain. We conclude that the C-terminus plays an important role in the efficient folding and regulation of ATP8A2.

The role of microtubules in transport between the endoplasmic reticulum and Golgi apparatus in mammalian cells.

2005 ◽  
Vol 72 ◽  
pp. 1-13 ◽  
Author(s):  
Krysten J. Palmer ◽  
Peter Watson ◽  
David J. Stephens
Keyword(s):  
Endoplasmic Reticulum ◽  
Mammalian Cells ◽  
Secretory Pathway ◽  
Motor Proteins ◽  
Microtubule Cytoskeleton ◽  
Early Secretory Pathway ◽  
Golgi Transport ◽  
Intracellular Compartments ◽  
Retrograde Traffic

The organization of intracellular compartments and the transfer of components between them are central to the correct functioning of mammalian cells. Proteins and lipids are transferred between compartments by the formation, movement and subsequent specific fusion of transport intermediates. These vesicles and membrane clusters must be coupled to the cytoskeleton and to motor proteins that drive motility. Anterograde ER (endoplasmic reticulum)-to-Golgi transport, and the converse step of retrograde traffic from the Golgi to the ER, are now known to involve coupling of membranes to the microtubule cytoskeleton. Here we shall discuss our current understanding of the mechanisms that link membrane traffic in the early secretory pathway to the microtubule cytoskeleton in mammalian cells. Recent data have also provided molecular detail of functional co-ordination of motor proteins to specify directionality, as well as mechanisms for regulating motor activity by protein phosphorylation.

An Insight Into Mitochondrial Dysfunction and its Implications in Neuro-logical Diseases

2020 ◽  
Vol 22 ◽  
Author(s):  
Asimul Islam ◽  
Anas Shamsi ◽  
Rashid Waseem ◽  
Syed Kazim
Keyword(s):  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorders ◽  
Large Body ◽  
Ros Generation ◽  
Cell Organelles ◽  
Ischemic Brain ◽  
Cellular Processes ◽  
Vital Cell ◽  
Insight Into

Abstract:: In the last few years, a massive increase in the research has been observed that focusses on investigating the role of mitochondria in pathogenesis of several neurodegenerative disorders. Mitochondria are vital cell organelles having im-portant roles in different cellular processes including energy production, calcium signaling, ROS generation, apoptosis, etc. Therefore, healthy mitochondria are necessary for cell survival and functioning. It would seem feasible that mitochondrial dysfunction will have implications in various pathological conditions. A large body of evidence indicates the role of mito-chondrion as a potential key player in the loss or dysfunction of neurons in various neurodegenerative disorders. In this review, we provide an insight into the mitochondrial dysfunction and its involvement in the pathology of several neurolog-ical diseases such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis, Hypoxic-Ischemic Brain Injury and many more.

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