Document Detail


Kaposi's sarcoma-associated herpesvirus-induced angiogenin plays roles in latency via the phospholipase C gamma pathway: blocking angiogenin inhibits latent gene expression and induces the lytic cycle.
MedLine Citation:
PMID:  21209106     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
During de novo infection of human dermal microvascular endothelial cells (HMVEC-d), Kaposi's sarcoma-associated herpesvirus (KSHV) induced the multifunctional angiogenin (ANG) protein, which entered the nuclei and nucleoli of infected cells and stimulated 45S rRNA gene transcription, proliferation, and tube formation, which were inhibited by blocking ANG nuclear translocation with the antibiotic neomycin (S. Sadagopan et al., J. Virol. 83:3342-3364, 2009). ANG was induced by KSHV latency protein LANA-1 (open reading frame 73 [ORF73]). Here we examined the presence and functions of ANG in KSHV-positive (KSHV(+)) primary effusion lymphoma (PEL/BCBL) cells. Significant ANG gene expression and secretion were observed in KSHV(+) (BCBL-1 and BC-3) and KSHV(+) and Epstein-Barr virus-positive (KSHV(+) EBV(+)) (JSC-1) PEL cells and in BJAB-KSHV cells but not in EBV(-) KSHV(-) lymphoma cells (Akata, Loukes, Ramos, and BJAB), EBV(+) lymphoma cells (Akata-EBV and Raji), and cells from an EBV(+) lymphoblastoid cell line, thus suggesting a specific association of ANG in KSHV biology. Inhibition of nuclear translocation of ANG resulted in reduced BCBL-1 and TIVE-LTC (latently infected endothelial) cell survival and proliferation, while EBV(-) and EBV(+) Akata cells were unaffected. Blocking nuclear transport of ANG inhibited latent ORF73 gene expression and increased lytic switch ORF50 gene expression, both during de novo infection and in latently infected cells. A greater quantity of infectious KSHV was detected in the supernatants of neomycin-treated BCBL-1 cells than 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated cells. Neomycin treatment and ANG silencing inhibited phospholipase Cγ (PLC-γ) and AKT phosphorylation, and in contrast, ANG induced ORF73 expression and PLC-γ and AKT phosphorylation. Further studies provided evidence that blockage of PLC-γ activation by neomycin appears to be mediating the inhibition of latent gene expression, since treatment with the conventional PLC-γ inhibitor U73122 also showed similar results. Silencing of ANG also resulted in reduced cell survival, reduced ORF73 gene expression, and lytic gene activation in BCBL-1 and TIVE-LTC cells and during de novo infection. Taken together, these studies suggest that KSHV has evolved to exploit ANG for its advantage via a so-far-unexplored PLC-γ pathway for maintaining its latency.
Authors:
Sathish Sadagopan; Mohanan Valiya Veettil; Nitika Paudel; Virginie Bottero; Bala Chandran
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-01-05
Journal Detail:
Title:  Journal of virology     Volume:  85     ISSN:  1098-5514     ISO Abbreviation:  J. Virol.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-02-18     Completed Date:  2011-04-11     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2666-85     Citation Subset:  IM    
Affiliation:
Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
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MeSH Terms
Descriptor/Qualifier:
Cells, Cultured
Endothelial Cells / virology
Gene Expression Profiling
Gene Expression Regulation, Viral*
Herpesvirus 4, Human / physiology
Herpesvirus 8, Human / physiology*
Host-Pathogen Interactions
Humans
Lymphoma, Primary Effusion / virology
Phospholipase C gamma / metabolism*
Ribonuclease, Pancreatic / metabolism*
Virus Latency*
Grant Support
ID/Acronym/Agency:
CA 075991/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
EC 3.1.27.-/angiogenin; EC 3.1.27.5/Ribonuclease, Pancreatic; EC 3.1.4.3/Phospholipase C gamma
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