scholarly journals Polyamines and eIF5A hypusination facilitate SREBP2 translation and cholesterol synthesis to enhance enterovirus attachment and infection

2021 ◽  
Author(s):  
Mason R Firpo ◽  
Marine J Petite ◽  
Natalie J LoMascolo ◽  
Priya Shah ◽  
Bryan C. Mounce
Keyword(s):  
Cholesterol Synthesis ◽  
Cellular Proliferation ◽  
Polymerase Activity ◽  
Cholesterol Homeostasis ◽  
Cellular Processes ◽  
Cellular Attachment ◽  
Cvb3 Infection ◽  
Cell Processes ◽  
A Cell ◽  
Cellular Transcription

Metabolism is key to cellular processes that ultimately underly the ability of a virus to productively infect a cell. Polyamines are small metabolites that are vital for many host cell processes including cellular proliferation, transcription, and translation, and these molecules are also key in virus infection. Depletion of polyamines inhibits viral infection via diverse mechanisms, including by inhibiting polymerase activity, cellular attachment, and translation of viral proteins. The precise mechanisms underlying many of these phenotypes remain to be understood. We have shown previously that Coxsackievirus B3 requires polyamines for attachment and protease function; however, the mechanism behind this is unknown. Here, we report that polyamines' involvement in translation, through a process called hypusination, globally affects expression of cholesterol synthesis genes by supporting SREBP2 translation, the master transcriptional regulator of cholesterol synthesis genes. By measuring bulk cellular transcription, we found that polyamines enhance the expression of a wide variety of cholesterol synthesis genes, ultimately regulated by SREBP2. The net effect of polyamine depletion on cells negatively impacts CVB3 attachment and replication in polyamine depleted cells by depleting cellular cholesterol. Exogenous cholesterol rescues CVB3 binding and replication, and mutant CVB3 resistant to polyamine depletion exhibits resistance to cholesterol perturbation. This study provides a novel link between polyamine synthesis and cholesterol homeostasis that explains data seen in animals and provides a mechanism through which polyamines impact CVB3 infection.

Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis

2007 ◽  
Vol 292 (2) ◽  
pp. L476-L486 ◽  
Author(s):  
Nicole M. White ◽  
Dechen Jiang ◽  
James D. Burgess ◽  
Ilya R. Bederman ◽  
Stephen F. Previs ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Cholesterol Synthesis ◽  
De Novo ◽  
Cholesterol Content ◽  
Cholesterol Homeostasis ◽  
Lysosomal Storage ◽  
In Vivo Models ◽  
Cellular Processes ◽  
Nasal Tissue

Determining how the regulation of cellular processes is impacted in cystic fibrosis (CF) is fundamental to understanding disease pathology and to identifying new therapeutic targets. In this study, unesterified cholesterol accumulation is observed in lung and trachea sections obtained from CF patients compared with non-CF tissues, suggesting an inherent flaw in cholesterol processing. An alternate staining method utilizing a fluorescent cholesterol probe also indicates improper lysosomal storage of cholesterol in CF cells. Excess cholesterol is also manifested by a significant increase in plasma membrane cholesterol content in both cultured CF cells and in nasal tissue excised from cftr −/− mice. Impaired intracellular cholesterol movement is predicted to stimulate cholesterol synthesis, a hypothesis supported by the observation of increased de novo cholesterol synthesis in lung and liver of cftr −/− mice compared with controls. Furthermore, pharmacological inhibition of cholesterol transport is sufficient to cause CF-like elevation in cytokine production in wild-type cells in response to bacterial challenge but has no effect in CF cells. These data demonstrate via multiple methods in both cultured and in vivo models that cellular cholesterol homeostasis is inherently altered in CF. This perturbation of cholesterol homeostasis represents a potentially important process in CF pathogenesis.

scholarly journals Integrated genomic analysis reveals regulatory pathways and dynamic landscapes of the tRNA transcriptome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zefang Sun ◽  
Jia Tan ◽  
Minqiong Zhao ◽  
Qiyao Peng ◽  
Mingqing Zhou ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Genomic Analysis ◽  
Rna Seq ◽  
Regulatory Pathways ◽  
Cellular Processes ◽  
Dynamic Landscapes ◽  
Rna Fragments ◽  
A Cell ◽  
Considerable Impact ◽  
New Algorithms

AbstracttRNAs and tRNA-derived RNA fragments (tRFs) play various roles in many cellular processes outside of protein synthesis. However, comprehensive investigations of tRNA/tRF regulation are rare. In this study, we used new algorithms to extensively analyze the publicly available data from 1332 ChIP-Seq and 42 small-RNA-Seq experiments in human cell lines and tissues to investigate the transcriptional and posttranscriptional regulatory mechanisms of tRNAs. We found that histone acetylation, cAMP, and pluripotency pathways play important roles in the regulation of the tRNA gene transcription in a cell-specific manner. Analysis of RNA-Seq data identified 950 high-confidence tRFs, and the results suggested that tRNA pools are dramatically distinct across the samples in terms of expression profiles and tRF composition. The mismatch analysis identified new potential modification sites and specific modification patterns in tRNA families. The results also show that RNA library preparation technologies have a considerable impact on tRNA profiling and need to be optimized in the future.

scholarly journals Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice

2008 ◽  
Vol 295 (1) ◽  
pp. G45-G53 ◽  
Author(s):  
Bin Hu ◽  
Lisa M. Colletti
Keyword(s):  
Stem Cell ◽  
Liver Injury ◽  
Stem Cell Factor ◽  
Cellular Proliferation ◽  
Hepatocyte Proliferation ◽  
Mrna Levels ◽  
Wild Type ◽  
Hepatocyte Apoptosis ◽  
Large Reservoir ◽  
A Cell

Stem cell factor (SCF) and its receptor c-kit are important in hematopoiesis and cellular proliferation. c-kit has also been identified as a cell surface marker for progenitor cells. We have previously shown that there is a large reservoir of hepatic SCF, and this molecule plays a significant role in liver regeneration after 70% hepatectomy. In the current study, we further examined the expression of SCF and c-kit in acetaminophen (APAP)-induced liver injury in C57BL/6J mice or SCF-deficient sl-sld mice and their appropriate wild-type controls. Following APAP-induced liver injury, c-kit mRNA expression increased, with peak levels detected 48 h postinjury. Hepatic SCF mRNA levels after APAP injury were also increased, with peak levels seen 16 h post-APAP. The mortality rate in SCF-deficient mice treated with APAP was significantly higher than that of wild-type mice; furthermore, administration of exogenous SCF significantly reduced the mortality of APAP-treated wild-type mice. Bromodeoxyuridine incorporation experiments showed that SCF significantly increased hepatocyte proliferation at 48 and 72 h in APAP-treated mice. SCF inhibited APAP-induced hepatocyte apoptosis and increased Bcl-2 and Bcl-xL expression, suggesting that this decrease in hepatocyte apoptosis is mediated through Bcl-2 and Bcl-xL. In summary, SCF and c-kit expression was increased after APAP-induced liver injury. Administration of exogenous SCF reduces mortality in APAP-treated mice, increases hepatocyte proliferation, and prevents hepatocyte apoptosis induced by APAP, suggesting that these molecules are important in the liver's recovery from these injuries.

scholarly journals Considerations when investigating lncRNA function in vivo

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Andrew R Bassett ◽  
Asifa Akhtar ◽  
Denise P Barlow ◽  
Adrian P Bird ◽  
Neil Brockdorff ◽  
...  
Keyword(s):  
Normal Cell ◽  
Regulatory Elements ◽  
Genomic Locus ◽  
Cellular Processes ◽  
Cell Processes ◽  
Non Coding Rnas ◽  
Per Se ◽  
Dna Regulatory Elements

Although a small number of the vast array of animal long non-coding RNAs (lncRNAs) have known effects on cellular processes examined in vitro, the extent of their contributions to normal cell processes throughout development, differentiation and disease for the most part remains less clear. Phenotypes arising from deletion of an entire genomic locus cannot be unequivocally attributed either to the loss of the lncRNA per se or to the associated loss of other overlapping DNA regulatory elements. The distinction between cis- or trans-effects is also often problematic. We discuss the advantages and challenges associated with the current techniques for studying the in vivo function of lncRNAs in the light of different models of lncRNA molecular mechanism, and reflect on the design of experiments to mutate lncRNA loci. These considerations should assist in the further investigation of these transcriptional products of the genome.

scholarly journals Mitochondrial Metabolism in Major Neurological Diseases

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 229 ◽  
Author(s):  
Zhengqiu Zhou ◽  
Grant Austin ◽  
Lyndsay Young ◽  
Lance Johnson ◽  
Ramon Sun
Keyword(s):  
Energy Production ◽  
Cellular Proliferation ◽  
Neurological Diseases ◽  
Mitochondrial Metabolism ◽  
Mitochondrial Activity ◽  
Disease Manifestation ◽  
Cellular Processes ◽  
Metabolic Dysregulation ◽  
Basic Functions ◽  
Regulation Functions

Mitochondria are bilayer sub-cellular organelles that are an integral part of normal cellular physiology. They are responsible for producing the majority of a cell’s ATP, thus supplying energy for a variety of key cellular processes, especially in the brain. Although energy production is a key aspect of mitochondrial metabolism, its role extends far beyond energy production to cell signaling and epigenetic regulation–functions that contribute to cellular proliferation, differentiation, apoptosis, migration, and autophagy. Recent research on neurological disorders suggest a major metabolic component in disease pathophysiology, and mitochondria have been shown to be in the center of metabolic dysregulation and possibly disease manifestation. This review will discuss the basic functions of mitochondria and how alterations in mitochondrial activity lead to neurological disease progression.

scholarly journals Chromatin regulates expression of small RNAs to help maintain transposon methylome homeostasis in Arabidopsis

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Ranjith K. Papareddy ◽  
Katalin Páldi ◽  
Subramanian Paulraj ◽  
Ping Kao ◽  
Stefan Lutzmayer ◽  
...  
Keyword(s):  
Growth And Development ◽  
Germ Line ◽  
Small Interfering Rnas ◽  
Chromatin States ◽  
Heterochromatin Formation ◽  
Cellular Processes ◽  
A Cell ◽  
Decondensed Chromatin ◽  
And Function ◽  
New Generation

Abstract Background Eukaryotic genomes are partitioned into euchromatic and heterochromatic domains to regulate gene expression and other fundamental cellular processes. However, chromatin is dynamic during growth and development and must be properly re-established after its decondensation. Small interfering RNAs (siRNAs) promote heterochromatin formation, but little is known about how chromatin regulates siRNA expression. Results We demonstrate that thousands of transposable elements (TEs) produce exceptionally high levels of siRNAs in Arabidopsis thaliana embryos. TEs generate siRNAs throughout embryogenesis according to two distinct patterns depending on whether they are located in euchromatic or heterochromatic regions of the genome. siRNA precursors are transcribed in embryos, and siRNAs are required to direct the re-establishment of DNA methylation on TEs from which they are derived in the new generation. Decondensed chromatin also permits the production of 24-nt siRNAs from heterochromatic TEs during post-embryogenesis, and siRNA production from bipartite-classified TEs is controlled by their chromatin states. Conclusions Decondensation of heterochromatin in response to developmental, and perhaps environmental, cues promotes the transcription and function of siRNAs in plants. Our results indicate that chromatin-mediated siRNA transcription provides a cell-autonomous homeostatic control mechanism to help reconstitute pre-existing chromatin states during growth and development including those that ensure silencing of TEs in the future germ line.

scholarly journals Influenza Virus and Chromatin: Role of the CHD1 Chromatin Remodeler in the Virus Life Cycle

2016 ◽  
Vol 90 (7) ◽  
pp. 3694-3707 ◽  
Author(s):  
Laura Marcos-Villar ◽  
Alejandra Pazo ◽  
Amelia Nieto
Keyword(s):  
Influenza Virus ◽  
Rna Polymerase Ii ◽  
Polymerase Activity ◽  
Virus Multiplication ◽  
Viral Transcription ◽  
Chromatin Remodeler ◽  
Viral Polymerase ◽  
Chromatin Dynamics ◽  
Rnap Ii ◽  
Cellular Transcription

ABSTRACTInfluenza A virus requires ongoing cellular transcription to carry out the cap-snatching process. Chromatin remodelers modify chromatin structure to produce an active or inactive conformation, which enables or prevents the recruitment of transcriptional complexes to specific genes; viral transcription thus depends on chromatin dynamics. Influenza virus polymerase associates with chromatin components of the infected cell, such as RNA polymerase II (RNAP II) or the CHD6 chromatin remodeler. Here we show that another CHD family member, CHD1 protein, also interacts with the influenza virus polymerase complex. CHD1 recognizes the H3K4me3 (histone 3 with a trimethyl group in lysine 4) histone modification, a hallmark of active chromatin. Downregulation of CHD1 causes a reduction in viral polymerase activity, viral RNA transcription, and the production of infectious particles. Despite the dependence of influenza virus on cellular transcription, RNAP II is degraded when viral transcription is complete, and recombinant viruses unable to degrade RNAP II show decreased pathogenicity in the murine model. We describe the CHD1–RNAP II association, as well as the parallel degradation of both proteins during infection with viruses showing full or reduced induction of degradation. The H3K4me3 histone mark also decreased during influenza virus infection, whereas a histone mark of inactive chromatin, H3K27me3, remained unchanged. Our results indicate that CHD1 is a positive regulator of influenza virus multiplication and suggest a role for chromatin remodeling in the control of the influenza virus life cycle.IMPORTANCEAlthough influenza virus is not integrated into the genome of the infected cell, it needs continuous cellular transcription to synthesize viral mRNA. This mechanism implies functional association with host genome expression and thus depends on chromatin dynamics. Influenza virus polymerase associates with transcription-related factors, such as RNA polymerase II, and with chromatin remodelers, such as CHD6. We identified the association of viral polymerase with another chromatin remodeler, the CHD1 protein, which positively modulated viral polymerase activity, viral RNA transcription, and virus multiplication. Once viral transcription is complete, RNAP II is degraded in infected cells, probably as a virus-induced mechanism to reduce the antiviral response. CHD1 associated with RNAP II and paralleled its degradation during infection with viruses that induce full or reduced degradation. These findings suggest that RNAP II degradation and CHD1 degradation cooperate to reduce the antiviral response.

scholarly journals Toxoplasma gondii Development of Its Replicative Niche: in Its Host Cell and Beyond

2014 ◽  
Vol 13 (8) ◽  
pp. 965-976 ◽  
Author(s):  
Ira J. Blader ◽  
Anita A. Koshy
Keyword(s):  
Toxoplasma Gondii ◽  
Host Cell ◽  
Host Cells ◽  
Content Type ◽  
Obligate Intracellular ◽  
Cellular Processes ◽  
High Prevalence ◽  
Life Threatening ◽  
Cell Processes ◽  
Cellular Pathways

ABSTRACTIntracellular pathogens can replicate efficiently only after they manipulate and modify their host cells to create an environment conducive to replication. While diverse cellular pathways are targeted by different pathogens, metabolism, membrane and cytoskeletal architecture formation, and cell death are the three primary cellular processes that are modified by infections.Toxoplasma gondiiis an obligate intracellular protozoan that infects ∼30% of the world's population and causes severe and life-threatening disease in developing fetuses, in immune-comprised patients, and in certain otherwise healthy individuals who are primarily found in South America. The high prevalence ofToxoplasmain humans is in large part a result of its ability to modulate these three host cell processes. Here, we highlight recent work defining the mechanisms by whichToxoplasmainteracts with these processes. In addition, we hypothesize why some processes are modified not only in the infected host cell but also in neighboring uninfected cells.

scholarly journals Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: The Autophagic- and Endo-Lysosomal Systems Go Extracellular

2020 ◽  
Vol 21 (7) ◽  
pp. 2576 ◽  
Author(s):  
Sandra Buratta ◽  
Brunella Tancini ◽  
Krizia Sagini ◽  
Federica Delo ◽  
Elisabetta Chiaradia ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cell Communication ◽  
Lysosomal Storage ◽  
Cellular Processes ◽  
Age Related ◽  
Extracellular Release ◽  
A Cell ◽  
Endosomal System

Beyond the consolidated role in degrading and recycling cellular waste, the autophagic- and endo-lysosomal systems play a crucial role in extracellular release pathways. Lysosomal exocytosis is a process leading to the secretion of lysosomal content upon lysosome fusion with plasma membrane and is an important mechanism of cellular clearance, necessary to maintain cell fitness. Exosomes are a class of extracellular vesicles originating from the inward budding of the membrane of late endosomes, which may not fuse with lysosomes but be released extracellularly upon exocytosis. In addition to garbage disposal tools, they are now considered a cell-to-cell communication mechanism. Autophagy is a cellular process leading to sequestration of cytosolic cargoes for their degradation within lysosomes. However, the autophagic machinery is also involved in unconventional protein secretion and autophagy-dependent secretion, which are fundamental mechanisms for toxic protein disposal, immune signalling and pathogen surveillance. These cellular processes underline the crosstalk between the autophagic and the endosomal system and indicate an intersection between degradative and secretory functions. Further, they suggest that the molecular mechanisms underlying fusion, either with lysosomes or plasma membrane, are key determinants to maintain cell homeostasis upon stressing stimuli. When they fail, the accumulation of undigested substrates leads to pathological consequences, as indicated by the involvement of autophagic and lysosomal alteration in human diseases, namely lysosomal storage disorders, age-related neurodegenerative diseases and cancer. In this paper, we reviewed the current knowledge on the functional role of extracellular release pathways involving lysosomes and the autophagic- and endo-lysosomal systems, evaluating their implication in health and disease.

Anticancer Drug Action on Poly(A) Polymerase Activity and Isoforms during Hela and Wish Cell Apoptosis

2000 ◽  
Vol 15 (2) ◽  
pp. 171-178 ◽  
Author(s):  
N.A.A. Balatsos ◽  
M. Havredaki ◽  
C.M. Tsiapalis
Keyword(s):  
Anticancer Agents ◽  
Enzyme Assay ◽  
Polymerase Activity ◽  
Activity Levels ◽  
Immunoblotting Analysis ◽  
A Cell ◽  
Lower Mobility ◽  
Cell Commitment ◽  
Diploid Cells ◽  
Mrna Polyadenylation

Poly(A) polymerase (PAP; EC 2.7.7.19) catalyzes mRNA polyadenylation. Its activity and isoform levels vary during cell cycle transformation and apoptosis. It has become widely accepted that cell death after DNA damage by anticancer agents is primarily the result of apoptosis and that cells able to evade apoptosis will be resistant to cell killing. The therapeutic agents interferon (IFN), 5-fluorouracil (5-FU) and tamoxifen (Tam) with different mechanisms of action mediate both partial dephosphorylation and inactivation of PAP, detected by immunoblotting analysis and PAP enzyme assay, respectively. We examined the apoptotic tendencies of HeLa and WISH cell lines caused by one of the drugs used, 5-FU. The trend in the cells examined, observed by DAPI and/or DNA fragmentation assay, was found to be accompanied by and reversibly related to PAP activity levels and PAP lower mobility phosphorylated forms of 106 and 100 kDa isoforms. Moreover, a cell type-modulated, differential response of HeLa (chemosensitive cells) versus WISH (drug-resistant diploid cells) has been revealed. This finding yields information on the possible use of PAP as a tumor marker involved in cell commitment and/or induction of apoptosis and may help to improve our understanding of tumor cell sensitivity to anticancer agents.

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