RRC ID 21527
Author Yoo J, Lee HN, Choi I, Choi D, Chung HK, Kim KE, Lee S, Aguilar B, Kang J, Park E, Lee YS, Maeng YS, Kim NY, Koh CJ, Hong YK.
Title Opposing regulation of PROX1 by interleukin-3 receptor and NOTCH directs differential host cell fate reprogramming by Kaposi sarcoma herpes virus.
Journal PLoS Pathog.
Abstract Lymphatic endothelial cells (LECs) are differentiated from blood vascular endothelial cells (BECs) during embryogenesis and this physiological cell fate specification is controlled by PROX1, the master regulator for lymphatic development. When Kaposi sarcoma herpes virus (KSHV) infects host cells, it activates the otherwise silenced embryonic endothelial differentiation program and reprograms their cell fates. Interestingly, previous studies demonstrated that KSHV drives BECs to acquire a partial lymphatic phenotype by upregulating PROX1 (forward reprogramming), but stimulates LECs to regain some BEC-signature genes by downregulating PROX1 (reverse reprogramming). Despite the significance of this KSHV-induced bidirectional cell fate reprogramming in KS pathogenesis, its underlying molecular mechanism remains undefined. Here, we report that IL3 receptor alpha (IL3Rα) and NOTCH play integral roles in the host cell type-specific regulation of PROX1 by KSHV. In BECs, KSHV upregulates IL3Rα and phosphorylates STAT5, which binds and activates the PROX1 promoter. In LECs, however, PROX1 was rather downregulated by KSHV-induced NOTCH signal via HEY1, which binds and represses the PROX1 promoter. Moreover, PROX1 was found to be required to maintain HEY1 expression in LECs, establishing a reciprocal regulation between PROX1 and HEY1. Upon co-activation of IL3Rα and NOTCH, PROX1 was upregulated in BECs, but downregulated in LECs. Together, our study provides the molecular mechanism underlying the cell type-specific endothelial fate reprogramming by KSHV.
Volume 8(6)
Pages e1002770
Published 2012
DOI 10.1371/journal.ppat.1002770
PMID 22719258
PMC PMC3375311
MeSH Cell Differentiation / physiology Cell Lineage Cells, Cultured Electrophoretic Mobility Shift Assay Endothelial Cells / metabolism Endothelial Cells / virology* Herpesviridae Infections / metabolism* Herpesvirus 8, Human / metabolism Homeodomain Proteins / metabolism* Humans Oligonucleotide Array Sequence Analysis Real-Time Polymerase Chain Reaction Receptors, Interleukin-3 / metabolism* Receptors, Notch / metabolism* Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Tumor Suppressor Proteins / metabolism*
IF 6.463
Times Cited 11
DNA material pAxCALNLhIL-3R alpha(forward) (RDB04994)