Human cytomegalovirus infection coopts chromatin organization to diminish TEAD1 transcription factor activity DOI Open Access

Khund Sayeed,

Sreeja Parameswaran, Matthew J. Beucler

et al.

Published: Nov. 27, 2024

Human cytomegalovirus (HCMV) infects up to 80% of the world’s population. Here, we show that HCMV infection leads widespread changes in human chromatin accessibility and looping, with hundreds thousands genomic regions affected 48 hours after infection. Integrative analyses reveal HCMV-induced perturbation Hippo signaling through drastic reduction TEAD1 transcription factor activity. We confirm extensive concordant loss binding, active H3K27ac histone marks, looping interactions upon Our data position at top a hierarchy involving multiple altered important developmental pathways. reduces activity four distinct mechanisms: closing TEAD1-bound chromatin, YAP1 phosphorylated levels, transcript protein alteration exon-6 usage. Altered TEAD1-based mechanisms are highly enriched genetic risk loci associated eye ear development, providing mechanistic insight into HCMV’s established roles these processes.

Language: Английский

Mechanistic Understanding of EBV+ Lymphoproliferative Disease Development After Transplantation DOI
Philippe L. Furlano, Georg A. Böhmig, Elisabeth Puchhammer‐Stöckl

et al.

Transplantation, Journal Year: 2024, Volume and Issue: 108(9), P. 1867 - 1881

Published: Feb. 5, 2024

Posttransplant lymphoproliferative disorders (PTLDs) are among the most common malignant complications after transplantation, leading to a drastic reduction in patient survival rates. The majority of PTLDs tightly linked Epstein-Barr virus (EBV+PTLDs) and result an uncontrolled proliferation EBV-infected cells. However, although EBV infections finding transplant recipients, patients with high loads will never develop EBV+PTLD. Natural killer cells EBV-specific CD8+ T lymphocytes critical for controlling cells, impairment these cytotoxic immune responses facilitates unfettered Recent years have seen considerable increase available literature aiming describe novel risk factors associated development EBV+PTLD, which may critically relate strength natural cell EBV-CD8+ lymphocyte responses. accumulation increased developing EBV+PTLD go hand hand. On one hand, factors, such as level immunosuppression or donor recipient serologic mismatch, distinct genetic host related affect other there is growing evidence that variants potential thus more likely induce Here, we aim review, from mechanistic point view, infecting explain why only minority recipients

Language: Английский

Citations

4
Inhibition of the Integrated stress response by Epstein-Barr virus oncoprotein LMP1 attenuates epithelial cell differentiation and lytic viral reactivation DOI Creative Commons
Deo R. Singh,

Yitao Zhang,

Stephen L. White

et al.

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(2), P. e1012934 - e1012934

Published: Feb. 14, 2025

EBV infects normal oral keratinocytes (NOKs) and plays an essential role in undifferentiated nasopharyngeal carcinoma (NPC). We previously showed that the oncogene, LMP1, promotes proliferation inhibits spontaneous differentiation telomerase-immortalized NOKs grown growth factor-restricted conditions. Here we have further examined phenotypes of infected with wild-type (WT EBV) versus LMP1-deleted mutant (ΔLMP1 RNA-seq results show WT EBV-infected not only reduced differentiation, but also decreased expression genes activated by integrated stress response (ISR) pathway, comparison to ΔLMP1 cells. The ISR pathway is mediated increased phosphorylation eIF2α translation initiation factor, leading most cellular proteins some proteins, including ATF4 CHOP. Immunoblot analyses confirmed uninfected cells LMP1 alone sufficient inhibit phosphorylation. found decreases activity two different kinases, PERK GCN2, NOKs, resulting ISR-induced transcription factors, CHOP, NOKs. Furthermore, both GCN2 are required for efficient TPA-induced lytic reactivation TPA-mediated epithelial cell differentiation. In addition, demonstrate over-expression CHOP induce NPC this effect activation differentiation-inducing KLF4 BLIMP1. Our suggest inhibition oncoprotein, may promote early development preventing reactivation.

Language: Английский

Citations

0
JAM-C prevents ocular fibrosis by suppressing the TAZ/KLF6 pathway DOI Creative Commons
Min Chen,

Wanhong Li,

Yuxiang Du

et al.

Journal of Advanced Research, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Language: Английский

Citations

0
Research landmarks on the 60th anniversary of Epstein-Barr virus DOI

Lan‐Yi Zhong,

Chu Xie, Lele Zhang

et al.

Science China Life Sciences, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 4, 2024

Language: Английский

Citations

3
The HPV8 E6 protein targets the Hippo and Wnt signaling pathways as part of its arsenal to restrain keratinocyte differentiation DOI Creative Commons

Sharon C. Wu,

Miranda Grace,

Karl Münger

et al.

mBio, Journal Year: 2023, Volume and Issue: 14(5)

Published: Sept. 7, 2023

Human papillomaviruses (HPVs) infect basal epithelial cells and cause a dramatic expansion of basal-like, proliferative cells. This reflects the ability to delay keratinocyte differentiation, thereby maintaining aspects cell identity persistently infected may enable establish maintain long-term infections in squamous tissues. Previous work has revealed that β-HPV8 E6 protein inhibit Notch transforming growth factor β signaling importantly contributes this activity. Here, we present evidence HPV8 also subverts Hippo Wnt these activities aid restraining differentiation.

Language: Английский

Citations

7
Human cytomegalovirus infection coopts chromatin organization to diminish TEAD1 transcription factor activity DOI Creative Commons

Khund Sayeed,

Sreeja Parameswaran, Matthew J. Beucler

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 13, 2024

Human cytomegalovirus (HCMV) infects up to 80% of the world's population. Here, we show that HCMV infection leads widespread changes in human chromatin accessibility and looping, with hundreds thousands genomic regions affected 48 hours after infection. Integrative analyses reveal HCMV-induced perturbation Hippo signaling through drastic reduction TEAD1 transcription factor activity. We confirm extensive concordant loss binding, active H3K27ac histone marks, looping interactions upon Our data position at top a hierarchy involving multiple altered important developmental pathways. reduces activity four distinct mechanisms: closing TEAD1-bound chromatin, YAP1 phosphorylated levels, transcript protein alteration

Language: Английский

Citations

1
Novel and multiple targets for chimeric antigen receptor-based therapies in lymphoma DOI Creative Commons
Yifan Pang, Nilanjan Ghosh

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: April 22, 2024

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 in B-cell non-Hodgkin lymphoma (NHL) validates the utility of CAR-based for lymphomatous malignancies. Despite success, treatment failure due to loss, mutation, or down-regulation remains main obstacle cure. On-target, off-tumor effect CD19-CAR T leads side effects such as prolonged aplasia, limiting application indolent diseases chronic lymphocytic leukemia (CLL). Alternative CAR targets and multi-specific are potential solutions improving cellular outcomes B-NHL. For Hodgkin lymphoma, several cell surface antigens have been studied targets, some which already showed promising results clinical trials. Some expressed by different lymphomas could be used designing tumor-agnostic CAR. Here, we reviewed that novel therapies, well CARs designed target two more lymphoma.

Language: Английский

Citations

1
Evidence of lesions from Epstein-Barr virus infection in human breast cancer genomes DOI Creative Commons
Bernard Friedenson

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 26, 2024

Abstract Epstein-Barr virus (EBV) infects essentially all humans and provides no benefit. EBV can cause nasopharyngeal cancer (NPC), Burkitt’s lymphoma (BL), perhaps breast cancer. Breast tissues from patients with are more likely to be EBV-positive than healthy controls. However, is not a proven of because the consistently EBV-positive. If causes cancer, it would have do without an active infection. Other cancers known viral origins require continuing presence virus. "hit run" theory difficult test for connection. Here, I this multiple independent bioinformatic analyses. First, hundreds genomes contained characteristic methylation scars that indicate cleared The had further differential hypermethylation near positions where reprograms normal cells into malignancy. Second, inactivated same tumor-suppressive mechanisms. Third, deletions were identified on chromosome 3p in shift oxidative glycolysis, prominent phenotype as Warburg effect. Similar found genomes. Fourth, somatic hypermutation clusters EBV-cancers marked genome translocations focal oncogene amplification. deregulation deaminase estrogen-induced topoisomerase explain these translocation breakpoints. Fifth, several alternate explanations results ruled out. Finally, only limited segments DNA matched human genome, making possible childhood vaccine end

Language: Английский

Citations

1
HPV18 E7 inhibits LATS1 kinase and activates YAP1 by degrading PTPN14 DOI Creative Commons
William J. Blakely, Joshua Hatterschide, Elizabeth White

et al.

mBio, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 9, 2024

ABSTRACT High-risk human papillomavirus (HPV) oncoproteins inactivate cellular tumor suppressors to reprogram host cell signaling pathways. HPV E7 proteins bind and degrade the suppressor PTPN14, thereby promoting nuclear localization of YAP1 oncoprotein inhibiting keratinocyte differentiation. is a transcriptional coactivator that drives epithelial stemness self-renewal. activity inhibited by highly conserved Hippo pathway, which frequently inactivated in cancers. MST1/2 LATS1/2 kinases form core kinase cascade. Active LATS1 phosphorylated on threonine 1079 inhibits phosphorylating it amino acids including serine 127. Here, we tested effect high-risk (carcinogenic) HPV18 pathway activity. We found either PTPN14 knockout or degradation decreased phosphorylation T1079 S127 keratinocytes Conversely, PTPN14-dependent differentiation required LATS certain PPxY motifs PTPN14. Neither nor putative phosphatase active sites were for promote Together, these data support inactivation reduce activity, IMPORTANCE The cascade YAP1, an driver There mounting evidence targeted viruses papillomavirus. promotes carcinogenic requires Blocking E7-dependent activation could inhibit HPV-mediated carcinogenesis, but mechanism activates has not been elucidated. Here report degrading kinase, reducing inhibitory YAP1. These can activate strengthen link between cells.

Language: Английский

Citations

1
The HPV8 E6 protein targets the Hippo and Wnt signaling pathways as part of its arsenal to restrain keratinocyte differentiation DOI Creative Commons

Sharon C. Wu,

Miranda Grace,

Karl Münger

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 24, 2023

ABSTRACT Infections with β-genus HPVs cause hyperplastic cutaneous lesions. In individuals the rare hereditary skin disease, epidermodysplasia verruciformis, such lesions can progress to squamous cell carcinomas (cSCC). β-HPV infections may also underlie cSCC development in chronically immunosuppressed individuals. Despite their prevalence and disease association, these viruses are not as well studied cancer-associated high-risk α-genus HPVs. HPV-associated characterized by a marked expansion of dividing, basal-like, poorly differentiated viral cells that contain genomes. This reflects ability inhibit epithelial differentiation which is likely driven need establish maintain long-term basal-like cells. Remarkably, β-HPVs accomplish this targeting different cellular effectors than It was previously reported HPV8 E6 protein restrains inhibiting Notch TGF-β signaling. Here we report subvert Hippo signaling activating TEAD transcriptional programs expression keratinocyte markers. Moreover, determined interfere gene triggered Wnt binding β-catenin-associated co-activator BCL9L serves restrain Hence has evolved remarkably large array mechanisms program infected IMPORTANCE Human papillomaviruses (HPVs) infect basal dramatic proliferative delay thereby maintaining aspects identity persistently enable tissues. Previous work revealed β-HPV8 NOTCH importantly contributes activity. present evidence subverts activities aid restraining differentiation.

Language: Английский

Citations

2