scholarly journals The Role of Phosphatidylinositol Phosphate Kinases during Viral Infection

Viruses ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 1124
Author(s):  
Anne Beziau ◽  
Denys Brand ◽  
Eric Piver
Keyword(s):  
Steady State ◽  
Viral Replication ◽  
Small Proportion ◽  
Membrane Dynamics ◽  
Concerted Action ◽  
Cellular Processes ◽  
Phosphatidylinositol Phosphate ◽  
Steady State Levels ◽  
Regulatory Functions

Phosphoinositides account for only a small proportion of cellular phospholipids, but have long been known to play an important role in diverse cellular processes, such as cell signaling, the establishment of organelle identity, and the regulation of cytoskeleton and membrane dynamics. As expected, given their pleiotropic regulatory functions, they have key functions in viral replication. The spatial restriction and steady-state levels of each phosphoinositide depend primarily on the concerted action of specific phosphoinositide kinases and phosphatases. This review focuses on a number of remarkable examples of viral strategies involving phosphoinositide kinases to ensure effective viral replication.

scholarly journals Murine Leukemia Virus Glycosylated Gag Reduces Murine SERINC5 Protein Expression at Steady-State Levels via the Endosome/Lysosome Pathway to Counteract SERINC5 Antiretroviral Activity

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Sunan Li ◽  
Iqbal Ahmad ◽  
Jing Shi ◽  
Bin Wang ◽  
Changqing Yu ◽  
...  
Keyword(s):  
Steady State ◽  
Viral Replication ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Live Cells ◽  
Receptor Mediated Endocytosis ◽  
Steady State Levels ◽  
Hiv 1 ◽  
Murine Leukemia

ABSTRACTGlycosylated Gag (glycoGag) is an accessory protein expressed by most gammaretroviruses, including murine leukemia virus (MLV). MLV glycoGag not only enhances MLV replication and disease progression but also increases human immunodeficiency virus type 1 (HIV-1) infectivity as Nef does. Recently, SERINC5 (Ser5) was identified as the target for Nef, and the glycoGag Nef-like activity has been attributed to the Ser5 antagonism. Here, we investigated how glycoGag antagonizes Ser5 using MLV glycoMA and murine Ser5 proteins. We confirm previous observations that glycoMA relocalizes Ser5 from plasma membrane to perinuclear punctated compartments and the important role of its Y36XXL39motif in this process. We find that glycoMA decreases Ser5 expression at steady-state levels and identify two other glycoGag crucial residues, P31 and R63, for the Ser5 downregulation. The glycoMA and Ser5 interaction is detected in live cells using a bimolecular fluorescence complementation assay. Ser5 is internalized via receptor-mediated endocytosis and relocalized to Rab5+early, Rab7+late, and Rab11+recycling endosomes by glycoMA. Although glycoMA is not polyubiquitinated, the Ser5 downregulation requires Ser5 polyubiquitination via the K48- and K63-linkage, resulting in Ser5 destruction in lysosomes. Although P31, Y36, L39, and R63 are not required for glycoMA interaction with Ser5, they are required for Ser5 relocalization to lysosomes for destruction. In addition, although murine Ser1, Ser2, and Ser3 exhibit very poor antiviral activity, they are also targeted by glycoMA for lysosomal destruction. We conclude that glycoGag has a broad activity to downregulate SERINC proteins via the cellular endosome/lysosome pathway, which promotes viral replication.IMPORTANCEMLV glycoGag not only enhances MLV replication but also increases HIV-1 infectivity similarly as Nef. Recent studies have discovered that both glycoGag and Nef antagonize a novel host restriction factor Ser5 and promote viral replication. Compared to Nef, the glycoGag antagonism of Ser5 is still poorly understood. MLV glycoGag is a transmembrane version of the structural Gag protein with an extra 88-amino-acid leader region that determines its activity. We now show that glycoGag interacts with Ser5 in live cells and internalizes Ser5 via receptor-mediated endocytosis. Ser5 is polyubiquitinated and relocalized to endosomes and lysosomes for massive destruction. In addition to the previously identified tyrosine-based sorting signal, we find two more important residues for Ser5 relocalization and downregulation. We also find that the Ser5 sensitivity to glycoGag is conserved in the SERINC family. Together, our findings highlight the important role of endosome/lysosome pathway in the enhancement of viral replication by viral proteins.

scholarly journals The critical role of T cells in glucocorticoid-induced osteoporosis

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Lin Song ◽  
Lijuan Cao ◽  
Rui Liu ◽  
Hui Ma ◽  
Yanan Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Steady State ◽  
Side Effects ◽  
Critical Role ◽  
Wild Type ◽  
Receptor Activator ◽  
Steady State Levels ◽  
Induced Apoptosis

AbstractGlucocorticoids (GC) are widely used clinically, despite the presence of significant side effects, including glucocorticoid-induced osteoporosis (GIOP). While GC are believed to act directly on osteoblasts and osteoclasts to promote osteoporosis, the detailed underlying molecular mechanism of GC-induced osteoporosis is still not fully elucidated. Here, we show that lymphocytes play a pivotal role in regulating GC-induced osteoporosis. We show that GIOP could not be induced in SCID mice that lack T cells, but it could be re-established by adoptive transfer of splenic T cells from wild-type mice. As expected, T cells in the periphery are greatly reduced by GC; instead, they accumulate in the bone marrow where they are protected from GC-induced apoptosis. These bone marrow T cells in GC-treated mice express high steady-state levels of NF-κB receptor activator ligand (RANKL), which promotes the formation and maturation of osteoclasts and induces osteoporosis. Taken together, these findings reveal a critical role for T cells in GIOP.

scholarly journals The Role of N6-Methyladenosine (m6A) Methylation Modifications in Hematological Malignancies

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 332
Author(s):  
Yan Zhao ◽  
Hongling Peng
Keyword(s):  
Bone Marrow ◽  
Pluripotent Stem Cells ◽  
Rna Splicing ◽  
Messenger Rna ◽  
Hematologic Malignancies ◽  
Cellular Processes ◽  
Proliferation And Differentiation ◽  
Regulatory Functions ◽  
Increased Susceptibility

Epigenetics is identified as the study of heritable modifications in gene expression and regulation that do not involve DNA sequence alterations, such as DNA methylation, histone modifications, etc. Importantly, N6-methyladenosine (m6A) methylation modification is one of the most common epigenetic modifications of eukaryotic messenger RNA (mRNA), which plays a key role in various cellular processes. It can not only mediate various RNA metabolic processes such as RNA splicing, translation, and decay under the catalytic regulation of related enzymes but can also affect the normal development of bone marrow hematopoiesis by regulating the self-renewal, proliferation, and differentiation of pluripotent stem cells in the hematopoietic microenvironment of bone marrow. In recent years, numerous studies have demonstrated that m6A methylation modifications play an important role in the development and progression of hematologic malignancies (e.g., leukemia, lymphoma, myelodysplastic syndromes [MDS], multiple myeloma [MM], etc.). Targeting the inhibition of m6A-associated factors can contribute to increased susceptibility of patients with hematologic malignancies to therapeutic agents. Therefore, this review elaborates on the biological characteristics and normal hematopoietic regulatory functions of m6A methylation modifications and their role in the pathogenesis of hematologic malignancies.

Role of myosin phosphorylation in contractility of a platelet aggregate

1985 ◽  
Vol 249 (3) ◽  
pp. C297-C303 ◽  
Author(s):  
M. E. Bromberg ◽  
R. W. Sevy ◽  
J. L. Daniel ◽  
L. Salganicoff
Keyword(s):  
Steady State ◽  
Light Chain ◽  
Myosin Phosphorylation ◽  
Nonmuscle Cells ◽  
Platelet Aggregate ◽  
Steady State Levels ◽  
State Contraction ◽  
The Relationship ◽  
Dose Dependent

The relationship between tension and myosin 20,000-Da light chain phosphorylation in intact nonmuscle cells was investigated using a preparation of thrombin-activated, irreversibly aggregated platelets known as the platelet strip. Steady-state levels of tension generated by the platelet strip were found to be linearly related to the level of myosin phosphorylation. This relationship was observed during dose-dependent relaxation induced by the adenylate cyclase activators prostaglandin (PG) E1 and PGI2, and during contraction induced by ADP, epinephrine, and the prostaglandin endoperoxide analogue U-46619, which did not appreciably alter the basal level of adenosine 3',5'-cyclic monophosphate in the preparation. The fully relaxed platelet strip, in the absence of external Ca2+, was associated with a level of 12% light chain phosphorylation, which increased to 72% on maximal contraction. During both relaxation and contraction, changes in myosin phosphorylation were also found to precede or coincide with tension changes. Furthermore, steady-state contraction induced by ADP was associated with a maintained elevation in the level of myosin phosphorylation. These results support the concept that myosin phosphorylation is an important regulatory mechanism for contractility in platelets.

scholarly journals Role of Human Sec63 in Modulating the Steady-State Levels of Multi-Spanning Membrane Proteins

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e49243 ◽  
Author(s):  
Andreas Mades ◽  
Katherina Gotthardt ◽  
Karin Awe ◽  
Jens Stieler ◽  
Tatjana Döring ◽  
...  
Keyword(s):  
Steady State ◽  
Membrane Proteins ◽  
Steady State Levels

scholarly journals lncRNA and Mechanisms of Drug Resistance in Cancers of the Genitourinary System

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2148 ◽  
Author(s):  
Dominik A. Barth ◽  
Jaroslav Juracek ◽  
Ondrej Slaby ◽  
Martin Pichler ◽  
George A. Calin
Keyword(s):  
Drug Resistance ◽  
Treatment Options ◽  
Cancer Therapies ◽  
Protein Coding ◽  
Genitourinary System ◽  
Cellular Processes ◽  
Rna Transcripts ◽  
Novel Therapeutic Strategies ◽  
Regulatory Functions

Available systemic treatment options for cancers of the genitourinary system have experienced great progress in the last decade. However, a large proportion of patients eventually develop resistance to treatment, resulting in disease progression and shorter overall survival. Biomarkers indicating the increasing resistance to cancer therapies are yet to enter clinical routine. Long non-coding RNAs (lncRNA) are non-protein coding RNA transcripts longer than 200 nucleotides that exert multiple types of regulatory functions of all known cellular processes. Increasing evidence supports the role of lncRNAs in cancer development and progression. Additionally, their involvement in the development of drug resistance across various cancer entities, including genitourinary malignancies, are starting to be discovered. Consequently, lncRNAs have been suggested as factors in novel therapeutic strategies to overcome drug resistance in cancer. In this review, the existing evidences on lncRNAs and their involvement in mechanisms of drug resistance in cancers of the genitourinary system, including renal cell carcinoma, bladder cancer, prostate cancer, and testicular cancer, will be highlighted and discussed to facilitate and encourage further research in this field. We summarize a significant number of lncRNAs with proposed pathways in drug resistance and available reported studies.

scholarly journals Positive-strand RNA viruses stimulate host phosphatidylcholine synthesis at viral replication sites

2016 ◽  
Vol 113 (8) ◽  
pp. E1064-E1073 ◽  
Author(s):  
Jiantao Zhang ◽  
Zhenlu Zhang ◽  
Vineela Chukkapalli ◽  
Jules A. Nchoutmboube ◽  
Jianhui Li ◽  
...  
Keyword(s):  
Viral Replication ◽  
Rna Viruses ◽  
Critical Role ◽  
Brome Mosaic Virus ◽  
Alternate Host ◽  
Positive Strand ◽  
Cellular Processes ◽  
Replication Sites ◽  
Positive Strand Rna

All positive-strand RNA viruses reorganize host intracellular membranes to assemble their viral replication complexes (VRCs); however, how these viruses modulate host lipid metabolism to accommodate such membrane proliferation and rearrangements is not well defined. We show that a significantly increased phosphatidylcholine (PC) content is associated with brome mosaic virus (BMV) replication in both natural host barley and alternate host yeast based on a lipidomic analysis. Enhanced PC levels are primarily associated with the perinuclear ER membrane, where BMV replication takes place. More specifically, BMV replication protein 1a interacts with and recruits Cho2p (choline requiring 2), a host enzyme involved in PC synthesis, to the site of viral replication. These results suggest that PC synthesized at the site of VRC assembly, not the transport of existing PC, is responsible for the enhanced accumulation. Blocking PC synthesis by deleting theCHO2gene resulted in VRCs with wider diameters than those in wild-type cells; however, BMV replication was significantly inhibited, highlighting the critical role of PC in VRC formation and viral replication. We further show that enhanced PC levels also accumulate at the replication sites of hepatitis C virus and poliovirus, revealing a conserved feature among a group of positive-strand RNA viruses. Our work also highlights a potential broad-spectrum antiviral strategy that would disrupt PC synthesis at the sites of viral replication but would not alter cellular processes.

scholarly journals Role of STE genes in the mating factor signaling pathway mediated by GPA1 in Saccharomyces cerevisiae.

1988 ◽  
Vol 8 (9) ◽  
pp. 3777-3783 ◽  
Author(s):  
N Nakayama ◽  
Y Kaziro ◽  
K Arai ◽  
K Matsumoto
Keyword(s):  
Steady State ◽  
Signaling Pathway ◽  
State Level ◽  
G1 Arrest ◽  
Gene Products ◽  
Mating Efficiency ◽  
Protein Functions ◽  
Steady State Levels ◽  
Mating Factor

The ste mutants (ste2, ste4, ste5, ste7, ste11, and ste12) are insensitive to mating factors and are, therefore, sterile. Roles of the STE gene products in the GPA1-mediated mating factor signaling pathway were studied by using ste gpa1 double mutants. Mating efficiency of a ste2 mutant defective in the alpha-factor receptor increased 1,000-fold in a gpa1 background, while G1 arrest and aberrant morphology (shmoo) caused by gpa1 were not suppressed by ste2. Furthermore, the steady-state level of the FUS1 transcript, which normally increases in response to mating factors, was also elevated when the GPA1 function was impaired. These results suggest that the GPA1 protein functions downstream of the STE2 receptor. Conversely, the sterility of ste4, ste5, ste7, ste11, and ste12 mutants was not suppressed by gpa1, but the lethal phenotype of gpa1 was suppressed by these ste mutations. Northern (RNA) blotting analysis revealed that the ste7, ste11, and ste12 mutations caused reductions of 50 to 70% in the steady-state levels of the GPA1 transcript, while ste4 had a slight effect and ste5 had no effect. This implies that the suppression by ste7, ste11, and ste12 could be due to reduced syntheses of additional components, including an effector, and that suppression by ste4 and ste5 may result from direct effects on the signaling pathway. The STE4, STE5, STE7, STE11, and STE12 products, therefore, appear to specify components of the signal transduction machinery, directly or indirectly, which function together with or downstream of GPA1.

scholarly journals Therapeutic Approaches and Role of ncRNAs in Cardiovascular Disorders and Insulin Resistance

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Kalupahana Irushi Pamodya Liyanage ◽  
Gamage Upeksha Ganegoda
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Cardiovascular Diseases ◽  
Gene Expression Regulation ◽  
Therapeutic Approaches ◽  
Gene Expressions ◽  
Diagnostic Biomarkers ◽  
Cellular Processes ◽  
Regulatory Functions

Diseases resulting from alterations in gene expressions through mutations in the genes or through changes in the gene expression regulation could be identified through the analysis of RNA expressions. ncRNAs play a significant role in regulation of the gene expression by controlling the expression levels of the coding RNAs and other cellular processes. Discoveries have shown that the human genome is encoded with sequences responsible for the transcription of thousands of ncRNAs. Even though the studies conducted on ncRNAs are still at initial stages, facts established so far display biomarkers that confirm their relationship with certain diseases such as cancers, cardiovascular diseases, and insulin resistance. These studies have been facilitated with high throughput modern sequencing techniques such as microarrays and RNA sequencing. The data obtained through the above analysis are processed with the aid of existing databases, to deduce conclusions on different diagnostic biomarkers and therapeutic targets for specific diseases. This review focuses on the association of ncRNAs in disease prediction, focusing mainly on cardiovascular diseases and disorders caused by insulin resistance. The report also analyzes regulatory functions of ncRNAs and novel approaches used in disease therapeutics.

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