scholarly journals Scrapie-like prion protein is translocated to the nuclei of infected cells independently of proteasome inhibition and interacts with chromatin

2004 ◽  
Vol 117 (11) ◽  
pp. 2411-2416 ◽  
Author(s):  
A. Mange
Keyword(s):  
Prion Protein ◽  
Proteasome Inhibition ◽  
Infected Cells

The inhibitory effect of the ScFv of an anti-prion protein antibody secreted from N2a58 cells on abnormal prion protein accumulation in scrapie-infected cells, ScN2a

Prions ◽  
2006 ◽  
pp. 255-255
Author(s):  
Yoshihisa Shimizu ◽  
Yuko Kaku-Ushiki ◽  
Shigeo Fukuda ◽  
Morikazu Shinagawa ◽  
Takashi Yokoyama ◽  
...  
Keyword(s):  
Prion Protein ◽  
Inhibitory Effect ◽  
Protein Accumulation ◽  
Infected Cells

Biosynthesis of the Scrapie Prion Protein in Scrapie-Infected Cells

1993 ◽  
pp. 199-200
Author(s):  
A. Taraboulos ◽  
D. R. Borchelt ◽  
A. Raeber ◽  
D. Avrahami ◽  
S. B. Prusiner
Keyword(s):  
Prion Protein ◽  
Infected Cells

scholarly journals Mitochondrial Cell Death Suppressors Carried by Human and Murine Cytomegalovirus Confer Resistance to Proteasome Inhibitor-Induced Apoptosis

2005 ◽  
Vol 79 (19) ◽  
pp. 12205-12217 ◽  
Author(s):  
A. Louise McCormick ◽  
Christopher D. Meiering ◽  
Geoffrey B. Smith ◽  
Edward S. Mocarski
Keyword(s):  
Cell Death ◽  
Viral Genome ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibition ◽  
Murine Cytomegalovirus ◽  
Viral Inhibitor ◽  
Infected Cells ◽  
Induced Apoptosis ◽  
Functional Copy ◽  
Inactivating Mutations

ABSTRACT Human cytomegalovirus carries a mitochondria-localized inhibitor of apoptosis (vMIA) that is conserved in primate cytomegaloviruses. We find that inactivating mutations within UL37x1, which encodes vMIA, do not substantially affect replication in TownevarATCC (Towne-BAC), a virus that carries a functional copy of the betaherpesvirus-conserved viral inhibitor of caspase 8 activation, the UL36 gene product. In Towne-BAC infection, vMIA reduces susceptibility of infected cells to intrinsic death induced by proteasome inhibition. vMIA is sufficient to confer resistance to proteasome inhibition when expressed independent of viral infection. Murine cytomegalovirus m38.5, whose position in the viral genome is analogous to UL37x1, exhibits mitochondrial association and functions in much the same manner as vMIA in inhibiting intrinsic cell death. This work suggests a common role for vMIA in rodent and primate cytomegaloviruses, modulating the threshold of virus-infected cells to intrinsic cell death.

scholarly journals HIV Protease-Generated Casp8p41, When Bound and Inactivated by Bcl2, Is Degraded by the Proteasome

2018 ◽  
Vol 92 (13) ◽  
Author(s):  
Sekar Natesampillai ◽  
Nathan W. Cummins ◽  
Zilin Nie ◽  
Rahul Sampath ◽  
Jason V. Baker ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibition ◽  
Hiv Protease ◽  
Dependent Manner ◽  
Clinical Use ◽  
Protease Cleavage ◽  
Infected Cells ◽  
Memory Cd4 T Cells

ABSTRACTHIV protease is known to cause cell death, which is dependent upon cleavage of procaspase 8. HIV protease cleavage of procaspase 8 generates Casp8p41, which directly binds Bak with nanomolar affinity, causing Bak activation and consequent cell death. Casp8p41 can also bind Bcl2 with nanomolar affinity, in which case cell death is averted. Central memory CD4 T cells express high levels of Bcl2, possibly explaining why those cells do not die when they reactivate HIV. Here, we determine that the Casp8p41-Bcl2 complex is polyubiquitinated and degraded by the proteasome. Ixazomib, a proteasome inhibitor in clinical use, blocks this pathway, increasing the abundance of Casp8p41 and causing more cells to die in a Casp8p41-dependent manner.IMPORTANCEThe Casp8p41 pathway of cell death is unique to HIV-infected cells yet is blocked by Bcl2. Once bound by Bcl2, Casp8p41 is polyubiquitinated and degraded by the proteasome. Proteasome inhibition blocks degradation of Casp8p41, increasing Casp8p41 levels and causing more HIV-infected cells to die.

scholarly journals Evidence that the Human Cytomegalovirus IE2-86 Protein Binds mdm2 and Facilitates mdm2 Degradation

2006 ◽  
Vol 80 (8) ◽  
pp. 3833-3843 ◽  
Author(s):  
Zhigang Zhang ◽  
David L. Evers ◽  
Joseph F. McCarville ◽  
Jean-Christophe Dantonel ◽  
Shu-Mei Huong ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Half Life ◽  
Proteasome Inhibition ◽  
Loss Of Function ◽  
Free System ◽  
A Cell ◽  
Infected Cells ◽  
Interfering Rna ◽  
P53 Tumor Suppressor Protein ◽  
Putative Zinc Finger

ABSTRACT Levels of the p53 tumor suppressor protein are increased in human cytomegalovirus (HCMV)-infected cells and may be important for HCMV pathogenesis. In normal cells p53 levels are kept low due to an autoregulatory feedback loop where p53 activates the transcription of mdm2 and mdm2 binds and ubiquitinates p53, targeting p53 for proteasomal degradation. Here we report that, in contrast to uninfected cells, mdm2 was undetectable upon treatment of infected fibroblasts with the proteasome inhibitor MG132. Cellular depletion of mdm2 was reproducible in p53-null cells transfected with the HCMV IE2-86 protein, but not with IE172, independently of the endogenous mdm2 promoter. IE2-86 also prevented the emergence of presumably ubiquitinated species of p53. The regions of IE2-86 important for mdm2 depletion were those containing the sequences corresponding to the putative zinc finger and C-terminal acidic motifs. mdm2 and IE2-86 coimmunoprecipitated in transfected and infected cell lysates and in a cell-free system. IE2-86 blocked mdm2's p53-independent transactivation of the cyclin A promoter in transient-transfection experiments. Pulse-chase experiments revealed that IE2-86 but not IE1-72 or several loss-of-function IE2-86 mutants increased the half-life of p53 and reduced the half-life of mdm2. Short interfering RNA-mediated depletion of IE2-86 restored the ability of HCMV-infected cells to accumulate mdm2 in response to proteasome inhibition. Taken together, the data suggest that specific interactions between IE2-86 and mdm2 cause proteasome-independent degradation of mdm2 and that this may be important for the accumulation of p53 in HCMV-infected cells.

scholarly journals Neurotropic influenza A virus infection causes prion protein misfolding into infectious prions in neuroblastoma cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hideyuki Hara ◽  
Junji Chida ◽  
Keiji Uchiyama ◽  
Agriani Dini Pasiana ◽  
Etsuhisa Takahashi ◽  
...  
Keyword(s):  
Prion Protein ◽  
Influenza A Virus ◽  
Protein Misfolding ◽  
Influenza A ◽  
Prion Diseases ◽  
Neuroblastoma Cells ◽  
Cellular Prion Protein ◽  
Infected Cells ◽  
Hit And Run

AbstractMisfolding of the cellular prion protein, PrPC, into the amyloidogenic isoform, PrPSc, which forms infectious protein aggregates, the so-called prions, is a key pathogenic event in prion diseases. No pathogens other than prions have been identified to induce misfolding of PrPC into PrPSc and propagate infectious prions in infected cells. Here, we found that infection with a neurotropic influenza A virus strain (IAV/WSN) caused misfolding of PrPC into PrPSc and generated infectious prions in mouse neuroblastoma cells through a hit-and-run mechanism. The structural and biochemical characteristics of IAV/WSN-induced PrPSc were different from those of RML and 22L laboratory prions-evoked PrPSc, and the pathogenicity of IAV/WSN-induced prions were also different from that of RML and 22L prions, suggesting IAV/WSN-specific formation of PrPSc and infectious prions. Our current results may open a new avenue for the role of viral infection in misfolding of PrPC into PrPSc and formation of infectious prions.

The retention of prion protein in the endoplasmic reticulum prevents N2A cells from proteasome inhibition-induced cytotoxicity

2017 ◽  
Vol 491 (2) ◽  
pp. 500-507
Author(s):  
Shuping Fang ◽  
Ruixue Wang ◽  
Honghao Liu ◽  
Weiliang Zhuang ◽  
Zhen Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Prion Protein ◽  
Proteasome Inhibition ◽  
N2a Cells

scholarly journals HEPES inhibits the conversion of prion protein in cell culture

2011 ◽  
Vol 92 (5) ◽  
pp. 1244-1250 ◽  
Author(s):  
Karine Delmouly ◽  
Maxime Belondrade ◽  
Danielle Casanova ◽  
Ollivier Milhavet ◽  
Sylvain Lehmann
Keyword(s):  
Cell Culture ◽  
Prion Protein ◽  
Cell Biology ◽  
Culture Medium ◽  
Inhibitory Effect ◽  
Live Cells ◽  
Cell Culture Medium ◽  
Dependent Inhibition ◽  
Infected Cells ◽  
Significant Concentration

HEPES is a well-known buffering reagent used in cell-culture medium. Interestingly, this compound is also responsible for significant modifications of biological parameters such as uptake of organic molecules, alteration of oxidative stress mechanisms or inhibition of ion channels. While using cell-culture medium supplemented with HEPES on prion-infected cells, it was noticed that there was a significant concentration-dependent inhibition of accumulation of the abnormal isoform of the prion protein (PrPSc). This effect was present only in live cells and was thought to be related to modification of the PrP environment or biology. These results could modify the interpretation of cell-culture assays of prion therapeutic agents, as well as of previous cell biology results obtained in the field using HEPES buffers. This inhibitory effect of HEPES could also be exploited to prevent contamination or propagation of prions in cell culture.

scholarly journals Human cytomegalovirus interferes with signal transducer and activator of transcription (STAT) 2 protein stability and tyrosine phosphorylation

2008 ◽  
Vol 89 (10) ◽  
pp. 2416-2426 ◽  
Author(s):  
Vu Thuy Khanh Le ◽  
Mirko Trilling ◽  
Manuel Wilborn ◽  
Hartmut Hengel ◽  
Albert Zimmermann
Keyword(s):  
Tyrosine Phosphorylation ◽  
Human Cytomegalovirus ◽  
Proteasome Inhibition ◽  
Early Gene ◽  
Similar Degree ◽  
Signal Transducer ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Infected Cells ◽  
Hcmv Replication

We have investigated the role of signal transducer and activator of transcription (STAT) 2 during human cytomegalovirus (HCMV) replication and found that protein levels of STAT2 are downregulated. STAT2 downregulation was observed in HCMV clinical isolates and laboratory strains with the exception of strain Towne. The HCMV-induced loss of STAT2 protein occurred despite an increased accumulation of STAT2 mRNA; it required HCMV early gene expression. The decrease in STAT2 was sensitive to proteasome inhibition, suggesting degradation of STAT2 via the ubiquitin proteasome pathway. Notably, pUL27, the HCMV homologue of the mouse CMV pM27 protein, which mediates the selective proteolysis of STAT2, did not induce STAT2 downregulation. Moreover, preceding STAT2 degradation, alpha/beta interferon (IFN)-receptor-mediated tyrosine phosphorylation of STAT2 was inhibited in HCMV-infected cells. This effect was paralleled by impaired tyrosine activation of STAT1 and STAT3. Accordingly, IFNs affected the replication efficiency of STAT2 degrading and non-degrading HCMV strains to a similar degree. In summary, HCMV abrogates IFN receptor signalling at multiple checkpoints by independent mechanisms including UL27-independent degradation of STAT2 and a preceding blockade of STAT2 phosphorylation.

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