scholarly journals Low-density lipoprotein receptor (LDL-R) suppresses endogenous cholesterol synthesis pathway to oppose gammaherpesvirus replication in primary macrophages

2021 ◽  
Author(s):  
C. A. Aurubin ◽  
D. A. Knaack ◽  
D. Sahoo ◽  
V. L. Tarakanova
Keyword(s):  
Gene Expression ◽  
Cholesterol Synthesis ◽  
Viral Gene Expression ◽  
Low Density Lipoproteins ◽  
Viral Gene ◽  
Low Density ◽  
Protein Levels ◽  
Antiviral Effects ◽  
Endogenous Cholesterol

Gammaherpesviruses are ubiquitous pathogens that establish life-long infections in >95% of adults worldwide and are associated with several cancers. We showed that endogenous cholesterol synthesis supports gammaherpesvirus replication. However, the role of exogenous cholesterol exchange and signaling during infection remains poorly understood. Extracellular cholesterol is carried in the serum by several lipoproteins, including low-density lipoproteins (LDL). The LDL-receptor (LDL-R) mediates the endocytosis of these cholesterol-rich LDL particles into the cell, thereby supplying the cell with cholesterol. We found that LDL-R expression attenuates gammaherpesvirus replication during the early stages of the replication cycle, as evident by increased viral gene expression in LDL-R -/- primary macrophages. This was not observed in primary fibroblasts, indicating that the antiviral effects of LDL-R are cell type-specific. Increased viral gene expression in LDL-R -/- primary macrophages was due to increased activity of the endogenous cholesterol synthesis pathway. Intriguingly, despite type I interferon-driven increase in LDL-R mRNA levels in infected macrophages, protein levels of LDL-R continually decreased over the single cycle of viral replication. Thus, our study has uncovered an intriguing tug of war between the LDL-R-driven antiviral effect on cholesterol metabolism and the viral targeting of the LDL-R protein. Importance. LDL-R is a cell surface receptor that mediates the endocytosis of cholesterol-rich low density lipoproteins, allowing cells to acquire cholesterol exogenously. Several RNA viruses usurp LDL-R function to facilitate replication; however, the role of LDL-R in DNA virus infection remains unknown. Gammaherpesviruses are double-stranded DNA viruses that are associated with several cancers. Here, we show that LDL-R attenuates gammaherpesvirus replication in primary macrophages by decreasing endogenous cholesterol synthesis activity, a pathway known to support gammaherpesvirus replication. In response, LDL-R protein levels are decreased in infected cells to mitigate the antiviral effects, revealing an intriguing tug-of-war between the virus and the host.

scholarly journals Glomerulosclerosis and viral gene expression in HIV-transgenic mice: Role of nef

2000 ◽  
Vol 58 (3) ◽  
pp. 1148-1159 ◽  
Author(s):  
Wataru Kajiyama ◽  
Jeffrey B. Kopp ◽  
Nancy J. Marinos ◽  
Paul E. Klotman ◽  
Peter Dickie
Keyword(s):  
Gene Expression ◽  
Transgenic Mice ◽  
Viral Gene Expression ◽  
Viral Gene

scholarly journals HAdV protein V core protein is targeted by the host SUMOylation machinery to limit essential viral functions

2017 ◽  
pp. JVI.01451-17 ◽  
Author(s):  
Nora Freudenberger ◽  
Tina Meyer ◽  
Peter Groitl ◽  
Thomas Dobner ◽  
Sabrina Schreiner
Keyword(s):  
Gene Expression ◽  
Core Protein ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Nuclear Pore ◽  
Independent Manner ◽  
Virus Growth ◽  
Core Proteins ◽  
Consensus Motifs

Human Adenoviruses (HAdV) are non-enveloped containing a linear, double-stranded DNA genome surrounded by an icosahedral capsid. To allow proper viral replication, the genome is imported through the nuclear-pore-complex associated with viral core proteins. Until now, the role of these incoming virion proteins during the early phase of infection was poorly understood.The core protein V is speculated to bridge core and the surrounding capsid. It binds the genome in a sequence-independent manner and localizes in the nucleus of infected cells, accumulating at nucleoli. Here, we show that protein V contains conserved SUMO conjugation motifs (SCMs). Mutation of these consensus motifs resulted in reduced SUMOylation of the protein; thus protein V represents a novel target of the host SUMOylation machinery. To understand the role of protein V SUMO posttranslational modification during productive HAdV infection, we generated a replication-competent HAdV with SCM mutations within the protein V coding sequence. Phenotypic analyses revealed that these SCM mutations are beneficial for adenoviral replication. Blocking protein V SUMOylation at specific sites shifts the onset of viral DNA replication to earlier time points during infection and promotes viral gene expression. Simultanously, these altered kinetics within the viral life cycle are accompanied by more efficient proteasomal degradation of host determinants and increased virus progeny production than observed during wildtype infection.Taken together, our studies show that protein V SUMOylation reduces virus growth; hence, protein V SUMOylation represents an important novel aspect of the host antiviral strategy to limit virus replication and thereby points to potential intervention strategies.ImportanceMany decades of research have revealed that HAdV structural proteins promote viral entry and mainly physical stability of the viral genome in the capsid. Our work over the last years showed that this concept needs expansion, as the functions are more diverse. We showed that capsid protein protein VI is regulating antiviral response by modulation of the transcription factor Daxx during infection. Moreover, core protein VII interacts with SPOC1 restriction factor, being beneficial for efficient viral gene expression. Here, we were able to show that also core protein V represents a novel substrate of the host SUMOylation machinery and contains several conserved SCMs; mutation of these consensus motifs reduced SUMOylation of the protein. Unexpectedly, we observed that introducing these mutations into HAdV promotes adenoviral replication. Conclusively, we offer novel insights into adenovirus core proteins and provide evidence that SUMOylation of HAdV factors regulates replication efficiency.

scholarly journals Dual role of the chromatin-binding factor PHF13 in the pre- and post-integration phases of HIV-1 replication

Open Biology ◽  
2017 ◽  
Vol 7 (10) ◽  
pp. 170115 ◽  
Author(s):  
Stephan Hofmann ◽  
Sandra Dehn ◽  
Ramona Businger ◽  
Sebastian Bolduan ◽  
Martha Schneider ◽  
...  
Keyword(s):  
Gene Expression ◽  
Functional Characterization ◽  
Viral Gene Expression ◽  
Dual Role ◽  
Replication Cycle ◽  
Viral Gene ◽  
Chromatin Binding ◽  
Viral Propagation ◽  
Hiv 1

Viruses interact with multiple host cell factors. Some of these are required to promote viral propagation, others have roles in inhibiting infection. Here, we delineate the function of the cellular factor PHF13 (or SPOC1), a putative HIV-1 restriction factor. Early in the HIV-1 replication cycle PHF13 increased the number of integrated proviral copies and the number of infected cells. However, after HIV-1 integration, high levels of PHF13 suppressed viral gene expression. The antiviral activity of PHF13 is counteracted by the viral accessory protein Vpr, which mediates PHF13 degradation. Altogether, the transcriptional master regulator and chromatin binding protein PHF13 does not have purely repressive effects on HIV-1 replication, but also promotes viral integration. By the functional characterization of the dual role of PHF13 during the HIV-1 replication cycle, we reveal a surprising and intricate mechanism through which HIV-1 might regulate the switch from integration to viral gene expression. Furthermore, we identify PHF13 as a cellular target specifically degraded by HIV-1 Vpr.

scholarly journals Human Cytomegalovirus Protein pp71 Displaces the Chromatin-Associated Factor ATRX from Nuclear Domain 10 at Early Stages of Infection

2008 ◽  
Vol 82 (24) ◽  
pp. 12543-12554 ◽  
Author(s):  
Vera Lukashchuk ◽  
Steven McFarlane ◽  
Roger D. Everett ◽  
Chris M. Preston
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Human Cytomegalovirus ◽  
Viral Gene Expression ◽  
Cellular Protein ◽  
Viral Gene ◽  
Nuclear Domain ◽  
Simplex Virus ◽  
Transformed Cell Lines

ABSTRACT The human cytomegalovirus (HCMV) tegument protein pp71, encoded by gene UL82, stimulates viral immediate-early (IE) transcription. pp71 interacts with the cellular protein hDaxx at nuclear domain 10 (ND10) sites, resulting in the reversal of hDaxx-mediated repression of viral transcription. We demonstrate that pp71 displaces an hDaxx-binding protein, ATRX, from ND10 prior to any detectable effects on hDaxx itself and that this event contributes to the role of pp71 in alleviating repression. Introduction of pp71 into cells by transfection, infection with a pp71-expressing herpes simplex virus type 1 vector, or by generation of transformed cell lines promoted the rapid relocation of ATRX from ND10 to the nucleoplasm without alteration of hDaxx levels or localization. A pp71 mutant protein unable to interact with hDaxx did not affect the intranuclear distribution of ATRX. Infection with HCMV at a high multiplicity of infection resulted in rapid displacement of ATRX from ND10, the effect being observed maximally by 2 h after adsorption, whereas infection with the UL82-null HCMV mutant ADsubUL82 did not affect ATRX localization even at 7 h postinfection. Cell lines depleted of ATRX by transduction with shRNA-expressing lentiviruses supported increased IE gene expression and virus replication after infection with ADsubUL82, demonstrating that ATRX has a role in repressing IE transcription. The results show that ATRX, in addition to hDaxx, is a component of cellular intrinsic defenses that limit HCMV IE transcription and that displacement of ATRX from ND10 by pp71 is important for the efficient initiation of viral gene expression.

scholarly journals Role of Notch Signal Transduction in Kaposi's Sarcoma-Associated Herpesvirus Gene Expression

2005 ◽  
Vol 79 (22) ◽  
pp. 14371-14382 ◽  
Author(s):  
Heesoon Chang ◽  
Dirk P. Dittmer ◽  
Shin-Young Chul ◽  
Youngkwon Hong ◽  
Jae U. Jung
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Transcription Factor ◽  
Binding Sites ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Lytic Gene ◽  
Lytic Gene Expression ◽  
Notch Signal

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) RTA transcription factor is recruited to its responsive elements through interaction with a Notch-mediated transcription factor, RBP-Jκ, indicating that RTA mimics cellular Notch signal transduction to activate viral lytic gene expression. To test whether cellular Notch signal transduction and RTA are functionally exchangeable for viral gene expression, human Notch intracellular (hNIC) domain that constitutively activates RBP-Jκ transcription factor activity was expressed in KSHV-infected primary effusion lymphoma BCBL1 cells (TRExBCBL1-hNIC) in a tetracycline-inducible manner. Gene expression profiling showed that like RTA, hNIC robustly induced expression of a number of viral genes, including viral interleukin 6 (vIL-6), K3, and K5. Unlike RTA, however, hNIC was not capable of evoking the full repertoire of lytic viral gene expression and thereby lytic replication. To further understand the role of Notch signal transduction in KSHV gene expression, vIL-6 growth factor and K5 immune modulator genes were selected for detailed analysis. Despite the presence of multiple RBP-Jκ binding sites, hNIC targeted the specific RBP-Jκ binding sites of vIL-6 and K5 promoter regions to regulate their gene expression. These results indicate that cellular Notch signal transduction not only is partially exchangeable with RTA in regard to activation of viral lytic gene expression but also provides a novel expression profile of KSHV growth and immune deregulatory genes that is likely different from that of RTA-independent standard latency program as well as RTA-dependent lytic reproduction program.

scholarly journals Detection of EBV Infection and Gene Expression in Oral Cancer from Patients in Taiwan by Microarray Analysis

2009 ◽  
Vol 2009 ◽  
pp. 1-15 ◽  
Author(s):  
Ching-Yu Yen ◽  
Min-Chi Lu ◽  
Ching-Cherng Tzeng ◽  
Jia-Yan Huang ◽  
Hsueh-Wei Chang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Oral Cancer ◽  
Epstein Barr Virus ◽  
Expression Patterns ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Barr Virus ◽  
Cancer Pathogenesis ◽  
Epstein Barr

Epstein-Barr virus is known to cause nasopharyngeal carcinoma. Although oral cavity is located close to the nasal pharynx, the pathogenetic role of Epstein-Barr virus (EBV) in oral cancers is unclear. This molecular epidemiology study uses EBV genomic microarray (EBV-chip) to simultaneously detect the prevalent rate and viral gene expression patterns in 57 oral squamous cell carcinoma biopsies (OSCC) collected from patients in Taiwan. The majority of the specimens (82.5%) were EBV-positive that probably expressed coincidently the genes for EBNAs, LMP2A and 2B, and certain structural proteins. Importantly, the genes fabricated at the spots 61 (BBRF1, BBRF2, and BBRF3) and 68 (BDLF4 and BDRF1) on EBV-chip were actively expressed in a significantly greater number of OSCC exhibiting exophytic morphology or ulceration than those tissues with deep invasive lesions (P=.0265and .0141, resp.). The results may thus provide the lead information for understanding the role of EBV in oral cancer pathogenesis.

scholarly journals A Computational Approach for Predicting Role of Human MicroRNAs in MERS-CoV Genome

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Md Mahmudul Hasan ◽  
Rozina Akter ◽  
Md. Shahin Ullah ◽  
Md. Jaynul Abedin ◽  
G. M. Ahsan Ullah ◽  
...  
Keyword(s):  
Gene Expression ◽  
Middle East ◽  
Viral Replication ◽  
Viral Gene Expression ◽  
Computational Approach ◽  
Viral Gene ◽  
Fatality Rate ◽  
Human Coronavirus ◽  
Cellular Mirnas

The new epidemic Middle East Respiratory Syndrome (MERS) is caused by a type of human coronavirus called MERS-CoV which has global fatality rate of about 30%. We are investigating potential antiviral therapeutics against MERS-CoV by using host microRNAs (miRNAs) which may downregulate viral gene expression to quell viral replication. We computationally predicted potential 13 cellular miRNAs from 11 potential hairpin sequences of MERS-CoV genome. Our study provided an interesting hypothesis that those miRNAs, that is, hsa-miR-628-5p, hsa-miR-6804-3p, hsa-miR-4289, hsa-miR-208a-3p, hsa-miR-510-3p, hsa-miR-18a-3p, hsa-miR-329-3p, hsa-miR-548ax, hsa-miR-3934-5p, hsa-miR-4474-5p, hsa-miR-7974, hsa-miR-6865-5p, and hsa-miR-342-3p, would be antiviral therapeutics against MERS-CoV infection.

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