Conserved linear motif within the immediate early protein ORF45 promotes its engagement with KSHV lytic cycle-promoting forkhead transcription factors, FOXK1 and FOXK2 DOI
M J Palmer, Alessandro De Leo, Natalie Atyeo

et al.

Journal of Virology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 17, 2024

ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus that can cause several cancers, such as Kaposi sarcoma and primary effusion lymphoma (PEL). We others have recently demonstrated Forkhead box (FOX) transcription factors be dysregulated by KSHV, they affect KSHV infection. Herein, we focus on dissecting the role of two FOXK subfamily members, FOXK1 FOXK2, in life cycle. proteins are key host regulators cellular functions, yet their infection remains unknown. Here, both essential for efficient lytic reactivation PEL cells. FOXK2 unique only FOX contain Forkhead-associated (FHA) domain. The FHA domain specialized protein binding recognizes short linear serine/threonine-rich (S/T) motif. Through an unbiased motif survey, found viral ORF45 its homologs putative FHA-binding immediate early tegument protein, vital virus production. uses novel conserved to interact with containing nucleus infected A single-point mutation threonine residue within abolished ORF45-FOXK1/2 interaction. Our data indicates encoded murine 68 (MHV68) Rhesus macaque rhadinovirus (RRV), domains sufficient interactions, highlighting mechanism. IMPORTANCE dysregulation contributes many different human diseases, including but impact lifecycle pathogenesis less understood. study uncovers critical pro-lytic function requirement PEL. bind using S/T Notably, even though gammaherpesviruses highly diverse, identified similar also showed evolutionary interaction between MHV68 RRV. provides basis future studies animal models evaluate interactions pathogenesis. Targeting these could allow way limit infections.

Language: Английский

Repurposing alcohol-abuse drug disulfiram for the treatment of KSHV-infected primary effusion lymphoma by activating antiviral innate immunity DOI Creative Commons
Lijie Wang, Zhenshan Liu,

Z.Z. Xu

et al.

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(3), P. e1012957 - e1012957

Published: March 4, 2025

Cancer remains a leading cause of global mortality, characterized by high treatment costs, and generally poor prognoses. Developing new anti-cancer drugs requires substantial investment, extended development timelines, failure rate. Therefore, repurposing existing US Food Drug Administration (FDA)-approved for other diseases as potential therapies offers faster more cost-effective approach. Primary effusion lymphoma (PEL) is an aggressive B-cell malignancy linked to Kaposi's sarcoma-associated herpesvirus (KSHV) infection. In this study, we identified that disulfiram (DSF), FDA-approved medication alcohol dependence, acts potent inhibitor KSHV-positive PEL. DSF suppresses PEL cell proliferation inducing apoptosis through the activation innate antiviral immunity. Remarkably, effectively impedes KSHV reactivation virion production in both endothelial cells. Inhibition TANK binding kinase 1 (TBK1) or interferon regulatory factor 3 (IRF3), essential activators immunity, reverses DSF's effects on survival reactivation. Furthermore, significantly hinders initiation progression tumors xenograft mouse model, with effect notably abolished TBK1 depletion. Our findings highlighted promising therapeutic agent targeting persistent infection treating tumors.

Language: Английский

Citations

0
Molecular mechanisms of viral oncogenesis in haematological malignancies: perspectives from metabolic reprogramming, epigenetic regulation and immune microenvironment remodeling DOI Creative Commons
Qing Xiao, Yi Liu, Xing‐sheng Shu

et al.

Experimental Hematology and Oncology, Journal Year: 2025, Volume and Issue: 14(1)

Published: May 10, 2025

Abstract Haematological malignancies are one of the most common tumors, with a rising incidence noted over recent decades. Viral infections play significant roles in pathogenesis these globally. This review delves into contributions various known viruses—specifically Epstein-Barr virus (EBV), human immunodeficiency (HIV), T-cell leukemia type 1 (HTLV-1), Kaposi’s sarcoma-associated herpesvirus (KSHV), cytomegalovirus (HCMV), hepatitis B (HBV), C (HCV), and papillomavirus (HPV)—in development haematological malignancies. These viruses shown to drive tumorigenesis through mechanisms, such as metabolic reprogramming, epigenetic modifications, remodeling immune microenvironment. By directly disrupting fundamental cellular functions altering pathways, foster an milieu that supports both viral persistence tumor growth. A thorough understanding oncogenic processes is crucial not only for etiological discovery but also developing targeted interventions. emphasizes need continued research specific ways manipulate host cell’s environments, aiming provide insights could guide future advancements treatment modalities.

Language: Английский

Citations

0
Association between human herpesvirus 8 and lipid profile in northwest China: A cross‐sectional study DOI
Jing-Zhan Zhang, Peng Wang, Tingting Li

et al.

Journal of Medical Virology, Journal Year: 2024, Volume and Issue: 96(8)

Published: Aug. 1, 2024

Abstract Human herpesvirus 8 (HHV‐8) infection shows obvious regional and ethnic differences. Although studies have shown that these differences may be associated with lipid metabolism, to date, no large‐scale explored this. This study the seropositivity rate of HHV‐8 among 2516 residents from 10 regions northwest China then correlates profile. The serological positivity was 15.6% all residents. seroprevalence ranged 11.2–27.6% different ethnicities. Across BMI levels, positive rates were 27.6%, 16.9%, 13.6% for a < 18.5, 18.5–24.9, ≥25, respectively. lower hypertensive people (12.6%) than non‐hypertensive (16.7%). Univariate logistic regression analyses revealed age, hypertension, systolic blood pressure, BMI, total cholesterol, high‐density lipoprotein cholesterol (HDL‐C) significantly correlated ( p 0.05). Multivariate analysis after adjusting confounding factors showed HDL‐C (odds ratio [OR]: 0.132, 95% confidence interval [CI], 0.082–0.212; 0.001) (OR: 0.959, CI 0.933–0.986; = 0.003) seropositivity. Subgroup concerning ethnicity, sex, or age demonstrated consistent relationship HDL‐C. results inconsistent in subgroups. However, Spearman's correlation between serum antibody titer levels linear seropositive individuals (ρ −0.080, 0.058). titers also not −0.015, 0.381). Low an independent risk factor infection, but there is significant titers.

Language: Английский

Citations

1
LKB1 suppresses KSHV reactivation and promotes primary effusion lymphoma progression DOI
Guanya Li, Yinan Li, Xinyu Tang

et al.

Journal of Virology, Journal Year: 2024, Volume and Issue: 98(9)

Published: Aug. 28, 2024

Viruses normally reprogram the host cell metabolic pathways as well sensors to facilitate their persistence. The serine-threonine liver kinase B1 (LKB1) is a master upstream of 5'-AMP-activated protein (AMPK) that senses energy status and therefore regulates intracellular homeostasis. Previous studies showed AMPK restricts Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication in endothelial cells during primary infection promotes effusion lymphoma (PEL) survival. However, role LKB1 KSHV reactivation KSHV-associated malignancies unclear. In this study, we found phosphorylated or activated KSHV-positive PEL cells. Mechanistically, KSHV-encoded vCyclin mediated activation cells, knockout ablated, while overexpression enhanced activation. Furthermore, knockdown inactivated induced reactivation, indicated by increased expression viral genes virions supernatants. Accordingly, inhibition functional pharmacologic inhibitor, Compound C, promoted either AMPKα1 efficiently death apoptosis both

Language: Английский

Citations

1
FOXO is involved in antimicrobial peptides expression during WSSV infection in Exopalaemon carinicauda DOI
Xiaoling Dai, Derun Quan, Libao Wang

et al.

Fish & Shellfish Immunology, Journal Year: 2023, Volume and Issue: 144, P. 109286 - 109286

Published: Dec. 13, 2023

Language: Английский

Citations

3
Conserved linear motif within the immediate early protein ORF45 promotes its engagement with KSHV lytic cycle-promoting forkhead transcription factors, FOXK1 and FOXK2 DOI
M J Palmer, Alessandro De Leo, Natalie Atyeo

et al.

Journal of Virology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 17, 2024

ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus that can cause several cancers, such as Kaposi sarcoma and primary effusion lymphoma (PEL). We others have recently demonstrated Forkhead box (FOX) transcription factors be dysregulated by KSHV, they affect KSHV infection. Herein, we focus on dissecting the role of two FOXK subfamily members, FOXK1 FOXK2, in life cycle. proteins are key host regulators cellular functions, yet their infection remains unknown. Here, both essential for efficient lytic reactivation PEL cells. FOXK2 unique only FOX contain Forkhead-associated (FHA) domain. The FHA domain specialized protein binding recognizes short linear serine/threonine-rich (S/T) motif. Through an unbiased motif survey, found viral ORF45 its homologs putative FHA-binding immediate early tegument protein, vital virus production. uses novel conserved to interact with containing nucleus infected A single-point mutation threonine residue within abolished ORF45-FOXK1/2 interaction. Our data indicates encoded murine 68 (MHV68) Rhesus macaque rhadinovirus (RRV), domains sufficient interactions, highlighting mechanism. IMPORTANCE dysregulation contributes many different human diseases, including but impact lifecycle pathogenesis less understood. study uncovers critical pro-lytic function requirement PEL. bind using S/T Notably, even though gammaherpesviruses highly diverse, identified similar also showed evolutionary interaction between MHV68 RRV. provides basis future studies animal models evaluate interactions pathogenesis. Targeting these could allow way limit infections.

Language: Английский

Citations

0