An oncogenic viral interferon regulatory factor upregulates CUB domain-containing protein 1 to promote angiogenesis by hijacking transcription factor lymphoid enhancer-binding factor 1 and metastasis suppressor CD82.
Animals
Carcinogenesis
Cell Movement
Gene Expression Regulation
Herpesvirus 8, Human
/ physiology
Human Umbilical Vein Endothelial Cells
Humans
Interferon Regulatory Factors
/ genetics
Kangai-1 Protein
/ genetics
Lymphoid Enhancer-Binding Factor 1
/ genetics
Male
Mice
Mice, Nude
Neovascularization, Pathologic
/ genetics
Sarcoma, Kaposi
/ genetics
Signal Transduction
Ubiquitin-Protein Ligases
Viral Proteins
/ genetics
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
02
09
2019
accepted:
09
06
2020
revised:
08
06
2020
pubmed:
20
6
2020
medline:
15
12
2021
entrez:
20
6
2020
Statut:
ppublish
Résumé
Kaposi's sarcoma (KS), a highly angiogenic and invasive vascular tumor, is the most common AIDS-associated cancer caused by KS-associated herpesvirus (KSHV) infection. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) contributes to KSHV-induced cell motility (PLoS Pathog. 15:e1007578, 2019). However, the role of vIRF1 in KSHV-induced angiogenesis remains unknown. Here, using two in vivo angiogenesis models including the chick chorioallantoic membrane assay (CAM) and the matrigel plug angiogenesis assay in mice, we show that vIRF1 promotes angiogenesis by upregulating CUB domain (for complement C1r/C1s, Uegf, Bmp1) containing protein 1 (CDCP1). Mechanistically, vIRF1 enhances the expression of transcription factor lymphoid enhancer-binding factor 1 (Lef1) and binds to Lef1 to promote CDCP1 transcription. Meanwhile, vIRF1 degrades metastasis suppressor CD82 through an ubiquitin-proteasome pathway by recruiting E3 ubiquitin ligase AMFR to CD82, which protects CDCP1 from CD82-mediated, palmitoylation-dependent degradation. CDCP1 activates AKT signaling, which is required for vIRF1-induced cell motility but not angiogenesis. Our results illustrate that, by hijacking Lef1 and CD82, vIRF1 upregulates CDCP1 to promote angiogenesis and cell invasion. These novel findings demonstrate the vIRF1 targets multiple cellular proteins and pathways to promote the pathogenesis of KS, which could be attractive therapeutic targets for KSHV-induced malignancies.
Identifiants
pubmed: 32555380
doi: 10.1038/s41418-020-0578-0
pii: 10.1038/s41418-020-0578-0
pmc: PMC7852890
doi:
Substances chimiques
CD82 protein, human
0
Interferon Regulatory Factors
0
Kangai-1 Protein
0
LEF1 protein, human
0
Lymphoid Enhancer-Binding Factor 1
0
Viral Proteins
0
viral interferon regulatory factors
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3289-3306Subventions
Organisme : NCI NIH HHS
ID : R01 CA197153
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213275
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE025465
Pays : United States
Commentaires et corrections
Type : ErratumIn
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