Sperm associated antigen 9 promotes oncogenic KSHV-encoded interferon regulatory factor-induced cellular transformation and angiogenesis by activating the JNK/VEGFA pathway

Kaposi's sarcoma (KS), caused by Kaposi's sarcoma-associated herpesvirus (KSHV), is a highly angioproliferative disseminated tumor of endothelial cells commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) mediates KSHV-induced cell motility (PLoS Pathog. 2019 Jan 30;15(1):e1007578). However, the role of vIRF1 in KSHV-induced cellular transformation and angiogenesis remains unknown. Here, we show that vIRF1 promotes angiogenesis by upregulating sperm associated antigen 9 (SPAG9) using two in vivo angiogenesis models including the chick chorioallantoic membrane assay (CAM) and the matrigel plug angiogenesis assay in mice. Mechanistically, vIRF1 interacts with transcription factor Lef1 to promote SPAG9 transcription. vIRF1-induced SPAG9 promotes the interaction of mitogen-activated protein kinase kinase 4 (MKK4) with JNK1/2 to increase their phosphorylation, resulting in enhanced VEGFA expression, angiogenesis, cell proliferation and migration. Finally, genetic deletion of ORF-K9 from KSHV genome abolishes KSHV-induced cellular transformation and impairs angiogenesis. Our results reveal that vIRF1 transcriptionally activates SPAG9 expression to promote angiogenesis and tumorigenesis via activating JNK/VEGFA signaling. These novel findings define the mechanism of KSHV induction of the SPAG9/JNK/VEGFA pathway and establish the scientific basis for targeting this pathway for treating KSHV-associated cancers.

Errataetall:

ErratumIn: PLoS Pathog. 2022 Jan 7;18(1):e1010232. - PMID 34995339

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:16

Enthalten in:

PLoS pathogens - 16(2020), 8 vom: 10. Aug., Seite e1008730

Sprache:

Englisch

Beteiligte Personen:

Li, Wan [VerfasserIn]
Wang, Fei [VerfasserIn]
Shi, Jiale [VerfasserIn]
Feng, Qi [VerfasserIn]
Chen, Yuheng [VerfasserIn]
Qi, Xiaoyu [VerfasserIn]
Wang, Cong [VerfasserIn]
Lu, Hongmei [VerfasserIn]
Lu, Zhongmou [VerfasserIn]
Jia, Xuemei [VerfasserIn]
Yan, Qin [VerfasserIn]
Gao, Shou-Jiang [VerfasserIn]
Lu, Chun [VerfasserIn]

Links:

Volltext

Themen:

Adaptor Proteins, Signal Transducing
EC 2.7.1.24
EC 2.7.11.24
Interferon Regulatory Factors
Journal Article
Mitogen-Activated Protein Kinase 8
Mitogen-Activated Protein Kinase 9
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
SPAG9 protein, human
VEGFA protein, human
Vascular Endothelial Growth Factor A
Viral Proteins
Viral interferon regulatory factors

Anmerkungen:

Date Completed 07.10.2020

Date Revised 07.01.2022

published: Electronic-eCollection

ErratumIn: PLoS Pathog. 2022 Jan 7;18(1):e1010232. - PMID 34995339

Citation Status MEDLINE

doi:

10.1371/journal.ppat.1008730

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM313518912