A5079421880- Cytomegalovirus and herpesvirus research
- RNA regulation and disease
- Herpesvirus Infections and Treatments
- Nuclear Structure and Function
- Signaling Pathways in Disease
- Virus-based gene therapy research
- RNA Research and Splicing
- HIV Research and Treatment
- Toxin Mechanisms and Immunotoxins
- interferon and immune responses
- Erythrocyte Function and Pathophysiology
- Viral gastroenteritis research and epidemiology
- Viral-associated cancers and disorders
- Toxoplasma gondii Research Studies
- Animal Virus Infections Studies
- Pneumocystis jirovecii pneumonia detection and treatment
- RNA Interference and Gene Delivery
- Enterobacteriaceae and Cronobacter Research
- Lipid Membrane Structure and Behavior
- Melanoma and MAPK Pathways
- Ocular Diseases and Behçet’s Syndrome
- DNA Repair Mechanisms
- Fullerene Chemistry and Applications
- Neonatal and Maternal Infections
- Down syndrome and intellectual disability research
Friedrich-Alexander-Universität Erlangen-Nürnberg
2012-2021
Bial (Portugal)
2010
Sam Rayburn Memorial Veterans Center
2010
National Audubon Society
2010
Universitätsklinikum Erlangen
2007
Nuclear egress of herpesvirus capsids through the nuclear envelope is mediated by multimeric complex (NEC). The human cytomegalovirus (HCMV) core NEC defined an interaction between membrane-anchored pUL50 and its co-factor pUL53, tightly associated heterodimeric corecruitment to envelope. Cellular proteins, such as p32/gC1qR, emerin protein kinase C (PKC), are recruited direct with for extension NEC. As a functionally important event, recruitment both viral cellular kinases leads...
ABSTRACT Protein kinases represent central and multifunctional regulators of a balanced virus-host interaction. Cyclin-dependent protein kinase 7 (CDK7) plays crucial regulatory roles in cell cycle transcription, both connected with the replication many viruses. Previously, we developed CDK7 inhibitor, LDC4297, that inhibits vitro nano-picomolar range. Novel data from kinome-wide evaluation (>330 profiled ) demonstrate selectivity. Importantly, provide first evidence for antiviral...
The nucleocytoplasmic egress of viral capsids is a rate-limiting step in the replication human cytomegalovirus (HCMV). As reported recently, an HCMV-specific nuclear complex composed and cellular proteins, particular protein kinases with capacity to induce destabilization lamina. Viral kinase pUL97 C (PKC) play important roles by phosphorylating several types lamins. Using mutants, we show that lamin-phosphorylating activity associated reorganization lamin A/C. Either or PKC has potential...
Herpesviral capsids are assembled in the host cell nucleus before being translocated into cytoplasm for further maturation. The crossing of nuclear envelope represents a major event that requires formation egress complex (NEC). Previous studies demonstrated human cytomegalovirus (HCMV) proteins pUL50 and pUL53, as well their homologs all members Herpesviridae, interact with each other at form heterodimeric core NEC. In order to characterize viral cellular protein content multimeric NEC,...
Nuclear replication of cytomegalovirus relies on elaborate mechanisms nucleocytoplasmic egress viral particles. Thus, the role two essential and conserved nuclear proteins, pUL50 pUL53, is pivotal. pUL53 heterodimerize form a core complex (NEC), which anchored to inner membrane provides scaffold for assembly multimeric viral-cellular NEC. Here, we report crystal structure pUL50-pUL53 heterodimer (amino acids 1-175 50-292, respectively) at 2.44 Å resolution. Both proteins adopt globular fold...
Human cytomegalovirus-encoded pUL50 and pUL53 belong to a group of conserved herpesviral nuclear proteins. This study describes: (i) the co-localization with components lamina such as lamins A/C lamin B receptor by double immunofluorescent staining, (ii) strong pUL50-mediated relocalization from diffuse pattern towards rim localization, (iii) direct interaction between pUL53, well protein kinase C (PKC), shown yeast two-hybrid co-immunoprecipitation analyses, (iv) in vitro phosphorylation...
The nuclear egress of cytomegaloviral capsids traversing the envelope is dependent on a locally restricted destabilization rigid lamina. It has been suggested that multi-component complex (NEC) formed comprised both viral and cellular proteins which act to recruit lamin-phosphorylating protein kinases. Recently, we reported lamina-associated human cytomegalovirus-encoded pUL50 pUL53, conserved among herpesviruses, interact with each other kinase C (PKC) in transfected cells. multiple...
The nuclear lamina lines the inner membrane providing a structural framework for nucleus. Cellular processes, such as envelope breakdown during mitosis or export of large ribonucleoprotein complexes, are functionally linked to disassembly lamina. In general, is mediated by phosphorylation, but precise molecular mechanism still not completely understood. Recently, we suggested novel egress herpesviral capsids which involves cellular isomerase Pin1. this study, focused on mechanistic details...
Nuclear egress of herpesvirus capsids is mediated by a multi-component nuclear complex (NEC) assembled heterodimer two essential viral core proteins. In the case human cytomegalovirus (HCMV), this NEC defined interaction between membrane-anchored pUL50 and its cofactor, pUL53. protein phosphorylation considered to be an important regulatory step, so study focused on respective role cellular kinases. Multiply phosphorylated varieties were detected Western blot Phos-tag analyses as resulting...
Human cytomegalovirus encodes a number of phosphorylation-regulated proteins, including the autophosphorylating protein kinase pUL97 and nuclear mRNA export factor pUL69. Recently, it was reported that inhibitor roscovitine induces an intranuclear aggregation pUL69 in infected fibroblasts. Here, we demonstrate pUL97-specific inhibitors induce similar aggregation. Furthermore, direct pUL69-pUL97 interaction demonstrated by coimmunoprecipitation analyses. Deletion mapping identified domains...
The nucleocytoplasmic export of cytomegaloviral capsids is regulated by formation a multi-component nuclear egress complex (NEC), essentially based on viral proteins pUL50 and pUL53. In this study, the generation recombinant human cytomegaloviruses, expressing tagged versions pUL53, enabled investigation NEC in infected primary fibroblasts. For these viruses, wild-type-like mode pUL50-pUL53 interaction recruitment both to envelope could be demonstrated. Importantly, was translocated from an...
Herpesviral capsids are assembled in the host cell nucleus and subsequently translocated to cytoplasm. During this process it has been demonstrated that human cytomegalovirus proteins pUL50 pUL53 interact form, together with other viral cellular proteins, nuclear egress complex at envelope. In study we provide evidence specific residues of a conserved N-terminal region determine its intranuclear interaction pUL53. silico evaluation biophysical analyses suggested forms regular secondary...
The pUL97 protein kinase encoded by human cytomegalovirus is a multifunctional determinant of the efficiency viral replication and phosphorylates as well cellular substrate proteins. Here, we report that expressed in two isoforms with molecular masses approximately 90 100 kDa. ORF UL97 comprises an unusual coding strategy five in-frame ATG start codons are contained within N-terminal 157 aa. Site-directed mutagenesis, transient expression point deletion mutants proteomic analyses accumulated...
The nuclear phase of herpesvirus replication is regulated through the formation regulatory multi-component protein complexes. Viral genomic followed by capsid assembly, DNA encapsidation and egress. latter has been studied intensely pointing to a viral core egress complex (NEC) that recruits multimeric assembly cellular factors for reorganization envelope. To date, mechanism association human cytomegalovirus (HCMV) capsids with NEC, which in turn initiates specific steps budding, remains...
Proteins can be conjugated covalently by ubiquitin or ubiquitin-like proteins, such as SUMO and ISG15. ISG15 is highly induced in viral infection, conjugation, termed ISGylation, plays important regulatory roles growth. Although ISGylation has been shown to negatively affect many viruses, including human cytomegalovirus (HCMV), countermeasures that might modulate are not well understood. In the present study, we show transmembrane protein encoded HCMV UL50 inhibits causing proteasomal...
The multifunctional protein kinase pUL97 of human cytomegalovirus (HCMV) strongly determines the efficiency virus replication. Previously, existence two isoforms that arise from alternative translational initiation and show a predominant nuclear localization was described. Two bipartite sequences, NLS1 NLS2, were identified in N terminus large isoform, whilst small isoform exclusively contained NLS2. current study found following: (i) HCMV-infected primary fibroblasts showed accumulations...
Human cytomegalovirus (HCMV) causes severe sequelae in immunocompromised hosts. Current antiviral therapies have serious adverse effects, with treatment many clinical settings problematic, making new therapeutic approaches necessary. We examined the vitro efficacy of small interfering RNAs (siRNAs) targeting HCMV gene transcripts UL54 (DNA polymerase), UL97 (protein kinase) and UL122/123 (immediate-early proteins) as inhibitors viral protein expression virus replication cell cultures. Two...