scholarly journals Targeted Regulation of Nuclear Lamins by Ubiquitin and Ubiquitin-Like Modifiers

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1340 ◽  
Author(s):  
Michael Blank
Keyword(s):  
Animal Cell ◽  
Premature Aging ◽  
Cellular Processes ◽  
Nuclear Lamins ◽  
Disease States ◽  
Essential Components ◽  
Wide Range ◽  
Nuclear Envelope Assembly ◽  
Distinct Disease ◽  
Premature Aging Syndromes

Nuclear lamins (NLs) are essential components of the animal cell nucleus involved in the regulation of a plethora of molecular and cellular processes. These include the nuclear envelope assembly and stability, mechanotransduction and chromatin organization, transcription, DNA replication, damage repair, and genomic integrity maintenance. Mutations in NLs can lead to the development of a wide range of distinct disease phenotypes, laminopathies, consisting of cardiac, neuromuscular, metabolic and premature aging syndromes. In addition, alterations in the expression of nuclear lamins were associated with different types of neoplastic diseases. Despite the importance and critical roles that NLs play in the diverse cellular activities, we only recently started to uncover the complexity of regulatory mechanisms governing their expression, localization and functions. This integrative review summarizes and discusses the recent findings on the emerging roles of ubiquitin and ubiquitin-like modifiers (ULMs) in the regulation of NLs, highlighting the intriguing molecular associations and cross-talks occurring between NLs and these regulatory molecules under physiological conditions and in the disease states.

scholarly journals Characterization of cell-cell communication in COVID-19 patients

2020 ◽  
Author(s):  
Yingxin Lin ◽  
Lipin Loo ◽  
Andy Tran ◽  
Cesar Moreno ◽  
Daniel Hesselson ◽  
...  
Keyword(s):  
Disease Severity ◽  
Cell Communication ◽  
Cell Interaction ◽  
Communication Patterns ◽  
Cell Interactions ◽  
Interaction Patterns ◽  
Disease States ◽  
Wide Range ◽  
Distinct Disease ◽  
Cell Cell

AbstractCOVID-19 patients display a wide range of disease severity, ranging from asymptomatic to critical symptoms with high mortality risk. Our ability to understand the interaction of SARS-CoV-2 infected cells within the lung, and of protective or dysfunctional immune responses to the virus, is critical to effectively treat these patients. Currently, our understanding of cell-cell interactions across different disease states, and how such interactions may drive pathogenic outcomes, is incomplete. Here, we developed a generalizable workflow for identifying cells that are differentially interacting across COVID-19 patients with distinct disease outcomes and use it to examine five public single-cell RNA-seq datasets with a total of 85 individual samples. By characterizing the cell-cell interaction patterns across epithelial and immune cells in lung tissues for patients with varying disease severity, we illustrate diverse communication patterns across individuals, and discover heterogeneous communication patterns among moderate and severe patients. We further illustrate patterns derived from cell-cell interactions are potential signatures for discriminating between moderate and severe patients.

Nanoparticles Functionalized with Venom-Derived Peptides and Toxins for Pharmaceutical Applications

2020 ◽  
Vol 21 (2) ◽  
pp. 97-109 ◽  
Author(s):  
Ana P. dos Santos ◽  
Tamara G. de Araújo ◽  
Gandhi Rádis-Baptista
Keyword(s):  
Oral Absorption ◽  
Current Data ◽  
Pharmacological Activities ◽  
Venom Peptides ◽  
Essential Components ◽  
Wide Range ◽  
Different Types ◽  
Direct Use ◽  
Animal Venoms ◽  
Pharmaceutical Biotechnology

Venom-derived peptides display diverse biological and pharmacological activities, making them useful in drug discovery platforms and for a wide range of applications in medicine and pharmaceutical biotechnology. Due to their target specificities, venom peptides have the potential to be developed into biopharmaceuticals to treat various health conditions such as diabetes mellitus, hypertension, and chronic pain. Despite the high potential for drug development, several limitations preclude the direct use of peptides as therapeutics and hamper the process of converting venom peptides into pharmaceuticals. These limitations include, for instance, chemical instability, poor oral absorption, short halflife, and off-target cytotoxicity. One strategy to overcome these disadvantages relies on the formulation of bioactive peptides with nanocarriers. A range of biocompatible materials are now available that can serve as nanocarriers and can improve the bioavailability of therapeutic and venom-derived peptides for clinical and diagnostic application. Examples of isolated venom peptides and crude animal venoms that have been encapsulated and formulated with different types of nanomaterials with promising results are increasingly reported. Based on the current data, a wealth of information can be collected regarding the utilization of nanocarriers to encapsulate venom peptides and render them bioavailable for pharmaceutical use. Overall, nanomaterials arise as essential components in the preparation of biopharmaceuticals that are based on biological and pharmacological active venom-derived peptides.

scholarly journals Bend, Push, Stretch: Remarkable Structure and Mechanics of Single Intermediate Filaments and Meshworks

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1960
Author(s):  
K. Tanuj Sapra ◽  
Ohad Medalia
Keyword(s):  
Intermediate Filaments ◽  
Eukaryotic Cell ◽  
Coiled Coils ◽  
Cellular Functions ◽  
Mechanical Pressure ◽  
Mechanical Feature ◽  
Cellular Processes ◽  
Nuclear Lamins ◽  
Filament Networks ◽  
And Function

The cytoskeleton of the eukaryotic cell provides a structural and functional scaffold enabling biochemical and cellular functions. While actin and microtubules form the main framework of the cell, intermediate filament networks provide unique mechanical properties that increase the resilience of both the cytoplasm and the nucleus, thereby maintaining cellular function while under mechanical pressure. Intermediate filaments (IFs) are imperative to a plethora of regulatory and signaling functions in mechanotransduction. Mutations in all types of IF proteins are known to affect the architectural integrity and function of cellular processes, leading to debilitating diseases. The basic building block of all IFs are elongated α-helical coiled-coils that assemble hierarchically into complex meshworks. A remarkable mechanical feature of IFs is the capability of coiled-coils to metamorphize into β-sheets under stress, making them one of the strongest and most resilient mechanical entities in nature. Here, we discuss structural and mechanical aspects of IFs with a focus on nuclear lamins and vimentin.

scholarly journals Intracellular Ionic Strength Sensing Using NanoLuc

2021 ◽  
Vol 22 (2) ◽  
pp. 677
Author(s):  
Tausif Altamash ◽  
Wesam Ahmed ◽  
Saad Rasool ◽  
Kabir H. Biswas
Keyword(s):  
Thermal Stability ◽  
Phase Separation ◽  
Drug Discovery ◽  
Ionic Strength ◽  
Cellular Signaling ◽  
Live Cells ◽  
Protein Activity ◽  
Cellular Survival ◽  
Cellular Processes ◽  
Wide Range

Intracellular ionic strength regulates myriad cellular processes that are fundamental to cellular survival and proliferation, including protein activity, aggregation, phase separation, and cell volume. It could be altered by changes in the activity of cellular signaling pathways, such as those that impact the activity of membrane-localized ion channels or by alterations in the microenvironmental osmolarity. Therefore, there is a demand for the development of sensitive tools for real-time monitoring of intracellular ionic strength. Here, we developed a bioluminescence-based intracellular ionic strength sensing strategy using the Nano Luciferase (NanoLuc) protein that has gained tremendous utility due to its high, long-lived bioluminescence output and thermal stability. Biochemical experiments using a recombinantly purified protein showed that NanoLuc bioluminescence is dependent on the ionic strength of the reaction buffer for a wide range of ionic strength conditions. Importantly, the decrease in the NanoLuc activity observed at higher ionic strengths could be reversed by decreasing the ionic strength of the reaction, thus making it suitable for sensing intracellular ionic strength alterations. Finally, we used an mNeonGreen–NanoLuc fusion protein to successfully monitor ionic strength alterations in a ratiometric manner through independent fluorescence and bioluminescence measurements in cell lysates and live cells. We envisage that the biosensing strategy developed here for detecting alterations in intracellular ionic strength will be applicable in a wide range of experiments, including high throughput cellular signaling, ion channel functional genomics, and drug discovery.

Understanding Vascular Diseases: Lessons From Premature Aging Syndromes

2016 ◽  
Vol 32 (5) ◽  
pp. 650-658 ◽  
Author(s):  
Yuichi Ikeda ◽  
Hidetoshi Kumagai ◽  
Yoshihiro Motozawa ◽  
Jun-ichi Suzuki ◽  
Hiroshi Akazawa ◽  
...  
Keyword(s):  
Vascular Diseases ◽  
Premature Aging ◽  
Premature Aging Syndromes

scholarly journals The AAA+ ATPase p97, a cellular multitool

2017 ◽  
Vol 474 (17) ◽  
pp. 2953-2976 ◽  
Author(s):  
Lasse Stach ◽  
Paul S. Freemont
Keyword(s):  
Atp Hydrolysis ◽  
Current Status ◽  
Cellular Functions ◽  
Aaa Atpase ◽  
Cellular Processes ◽  
Proteotoxic Stress ◽  
Binding Domains ◽  
Wide Range ◽  
Aaa Atpases ◽  
Substrate Proteins

The AAA+ (ATPases associated with diverse cellular activities) ATPase p97 is essential to a wide range of cellular functions, including endoplasmic reticulum-associated degradation, membrane fusion, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and chromatin-associated processes, which are regulated by ubiquitination. p97 acts downstream from ubiquitin signaling events and utilizes the energy from ATP hydrolysis to extract its substrate proteins from cellular structures or multiprotein complexes. A multitude of p97 cofactors have evolved which are essential to p97 function. Ubiquitin-interacting domains and p97-binding domains combine to form bi-functional cofactors, whose complexes with p97 enable the enzyme to interact with a wide range of ubiquitinated substrates. A set of mutations in p97 have been shown to cause the multisystem proteinopathy inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia. In addition, p97 inhibition has been identified as a promising approach to provoke proteotoxic stress in tumors. In this review, we will describe the cellular processes governed by p97, how the cofactors interact with both p97 and its ubiquitinated substrates, p97 enzymology and the current status in developing p97 inhibitors for cancer therapy.

scholarly journals Autophagy is activated in the ovarian tissue of polycystic ovary syndrome

Reproduction ◽  
2018 ◽  
Vol 155 (1) ◽  
pp. 85-92 ◽  
Author(s):  
Da Li ◽  
Yue You ◽  
Fang-Fang Bi ◽  
Tie-Ning Zhang ◽  
Jiao Jiao ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Potential Role ◽  
Polycystic Ovary ◽  
Ovarian Tissue ◽  
Ovary Syndrome ◽  
Cellular Processes ◽  
Transmission Electron ◽  
Wide Range ◽  
Response To Stress

The importance of autophagy in polycystic ovary syndrome (PCOS)-related metabolic disorders is increasingly being recognized, but few studies have investigated the role of autophagy in PCOS. Here, transmission electron microscopy demonstrated that autophagy was enhanced in the ovarian tissue from both humans and rats with PCOS. Consistent with this, ovarian granulosa cells from PCOS rats showed increases in the autophagy marker protein light chain 3B (LC3B), whereas levels of the autophagy substrate SQSTM1/p62 were decreased. In addition, the ratio of LC3-II/LC3-I was markedly elevated in human PCOS ovarian tissue compared with normal ovarian tissue. Real-time PCR arrays indicated that 7 and 34 autophagy-related genes were down- and up-regulated in human PCOS , Signal-Net, and regression analysis suggested that there are a wide range of interactions among these 41 genes, and a potential network based on EGFR, ERBB2, FOXO1, MAPK1, NFKB1, IGF1, TP53 and MAPK9 may be responsible for autophagy activation in PCOS. Systematic functional analysis of 41 differential autophagy-related genes indicated that these genes are highly involved in specific cellular processes such as response to stress and stimulus, and are linked to four significant pathways, including the insulin, ERBB, mTOR signaling pathways and protein processing in the endoplasmic reticulum. This study provides evidence for a potential role of autophagy disorders in PCOS in which autophagy may be an important molecular event in the pathogenesis of PCOS.

scholarly journals E-Cadherin Acts as a Regulator of Transcripts Associated with a Wide Range of Cellular Processes in Mouse Embryonic Stem Cells

PLoS ONE ◽  
2011 ◽  
Vol 6 (7) ◽  
pp. e21463 ◽  
Author(s):  
Francesca Soncin ◽  
Lisa Mohamet ◽  
Sarah Ritson ◽  
Kate Hawkins ◽  
Nicoletta Bobola ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Cellular Processes ◽  
Wide Range ◽  
E Cadherin

scholarly journals Structural and functional studies of pyruvate carboxylase regulation by cyclic di-AMP in lactic acid bacteria

2017 ◽  
Vol 114 (35) ◽  
pp. E7226-E7235 ◽  
Author(s):  
Philip H. Choi ◽  
Thu Minh Ngoc Vu ◽  
Huong Thi Pham ◽  
Joshua J. Woodward ◽  
Mark S. Turner ◽  
...  
Keyword(s):  
Binding Site ◽  
Conformational Changes ◽  
Pyruvate Carboxylase ◽  
Adenosine Monophosphate ◽  
Binding Mode ◽  
Functional Studies ◽  
Cellular Processes ◽  
Wide Range ◽  
A Site ◽  
Amp Inhibition

Cyclic di-3′,5′-adenosine monophosphate (c-di-AMP) is a broadly conserved bacterial second messenger that has been implicated in a wide range of cellular processes. Our earlier studies showed that c-di-AMP regulates central metabolism inListeria monocytogenesby inhibiting its pyruvate carboxylase (LmPC), a biotin-dependent enzyme with biotin carboxylase (BC) and carboxyltransferase (CT) activities. We report here structural, biochemical, and functional studies on the inhibition ofLactococcus lactisPC (LlPC) by c-di-AMP. The compound is bound at the dimer interface of the CT domain, at a site equivalent to that in LmPC, although it has a distinct binding mode in the LlPC complex. This binding site is not well conserved among PCs, and only a subset of these bacterial enzymes are sensitive to c-di-AMP. Conformational changes in the CT dimer induced by c-di-AMP binding may be the molecular mechanism for its inhibitory activity. Mutations of residues in the binding site can abolish c-di-AMP inhibition. InL. lactis, LlPC is required for efficient milk acidification through its essential role in aspartate biosynthesis. The aspartate pool inL. lactisis negatively regulated by c-di-AMP, and high aspartate levels can be restored by expression of a c-di-AMP–insensitive LlPC. LlPC has high intrinsic catalytic activity and is not sensitive to acetyl-CoA activation, in contrast to other PC enzymes.

scholarly journals Cooperative subunit dynamics modulate p97 function

2018 ◽  
Vol 116 (1) ◽  
pp. 158-167 ◽  
Author(s):  
Rui Huang ◽  
Zev A. Ripstein ◽  
John L. Rubinstein ◽  
Lewis E. Kay
Keyword(s):  
Bound State ◽  
Nmr Studies ◽  
Biologically Relevant ◽  
Aaa Atpase ◽  
Cellular Processes ◽  
Allosteric Communication ◽  
Functional Dynamics ◽  
Nmr Study ◽  
Wide Range

p97 is an essential hexameric AAA+ ATPase involved in a wide range of cellular processes. Mutations in the enzyme are implicated in the etiology of an autosomal dominant neurological disease in which patients are heterozygous with respect to p97 alleles, containing one copy each of WT and disease-causing mutant genes, so that, in vivo, p97 molecules can be heterogeneous in subunit composition. Studies of p97 have, however, focused on homohexameric constructs, where protomers are either entirely WT or contain a disease-causing mutation, showing that for WT p97, the N-terminal domain (NTD) of each subunit can exist in either a down (ADP) or up (ATP) conformation. NMR studies establish that, in the ADP-bound state, the up/down NTD equilibrium shifts progressively toward the up conformation as a function of disease mutant severity. To understand NTD functional dynamics in biologically relevant p97 heterohexamers comprising both WT and disease-causing mutant subunits, we performed a methyl-transverse relaxation optimized spectroscopy (TROSY) NMR study on a series of constructs in which only one of the protomer types is NMR-labeled. Our results show positive cooperativity of NTD up/down equilibria between neighboring protomers, allowing us to define interprotomer pathways that mediate the allosteric communication between subunits. Notably, the perturbed up/down NTD equilibrium in mutant subunits is partially restored by neighboring WT protomers, as is the two-pronged binding of the UBXD1 adaptor that is affected in disease. This work highlights the plasticity of p97 and how subtle perturbations to its free-energy landscape lead to significant changes in NTD conformation and adaptor binding.

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