Opposing regulation of PROX1 by interleukin-3 receptor and NOTCH directs differential host cell fate reprogramming by Kaposi sarcoma herpes virus.
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.
Department of Surgery, Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Jaehyuk
J
Yoo
Ha Neul
HN
Lee
Inho
I
Choi
Dongwon
D
Choi
Hee Kyoung
HK
Chung
Kyu Eui
KE
Kim
Sunju
S
Lee
Berenice
B
Aguilar
Jinjoo
J
Kang
Eunkyung
E
Park
Yong Suk
YS
Lee
Yong-Sun
YS
Maeng
Nam Yoon
NY
Kim
Chester J
CJ
Koh
Young-Kwon
YK
Hong
D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology*; D006566:Herpesviridae Infections / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D016185:Receptors, Interleukin-3 / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000098551:Prospero-Related Homeobox 1 Protein
D018398:Homeodomain Proteins; D016185:Receptors, Interleukin-3; D051880:Receptors, Notch; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein