Opposing Regulation of PROX1 by Interleukin-3 Receptor and NOTCH Directs Differential Host Cell Fate Reprogramming by Kaposi Sarcoma Herpes Virus

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.

The JAK-STAT Transcriptional Regulator, STAT-5, Activates the ATM DNA Damage Pathway to Induce HPV 31 Genome Amplification upon Epithelial Differentiation

“…Kaposi sarcoma herpes viruses (KSHV) [39] as well as human T cell lymphotropic virus-I (HTLV-I) activate STAT-5 during viral infections [40], while human immunodeficiency viruses (HIV) [41] suppress STAT-5 activity. Interestingly, these viruses also modulate the ATM DNA damage response but a linkage between the two pathways in these viral systems has not been described.…”

TH2 cells and their cytokines regulate formation and function of lymphatic vessels

“…We also used the SABiosciences' proprietary database (DECODE, DECipherment Of DNA Elements) to search for binding sites of STAT6 in the promoter of the prox-1 gene and discovered that both human and mouse prox-1 genes contain a binding motif for STAT6 in their promoter regions. Furthermore, our group recently reported that STAT5 regulates Prox-1 expression by directly binding to the prox-1 promoter 41 . Thus, it is plausible that STAT6 could also be a transcriptional regulator of Prox-1.…”

Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis

“…31 In doing so, apoA-I sustained lymphatic neovascularization in the presence of TNF. The present results are consistent with preincubation of LECs with apoA-I before TNF treatment reducing total TNF-R1 expression, including the receptor molecules at the cell surface, which confer cellular sensitivity to TNF, and in the Golgi, which is responsible for replenishing cell surface TNF-R1 levels.…”