Deregulation of HDAC5 by Viral Interferon Regulatory Factor 3 Plays an Essential Role in Kaposi's Sarcoma-Associated Herpesvirus-Induced Lymphangiogenesis

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi’s sarcoma (KS), which is one of the most common HIV-associated neoplasms. The endothelium is the thin layer of squamous cells where vascular blood endothelial cells (BECs) line the interior surface of blood vessels and lymphatic endothelial cells (LECs) are in direct contact with lymphatic vessels. The KS lesions contain a prominent compartment of neoplastic spindle morphology cells that are closely related to LECs. Furthermore, while KSHV can infect both LECs and BECs in vitro, its infection activates genetic programming related to lymphatic endothelial cell fate, suggesting that lymphangiogenic pathways are involved in KSHV infection and malignancy. Here, we report for the first time that viral interferon regulatory factor 3 (vIRF3) is readily detected in over 40% of KS lesions and that vIRF3 functions as a proangiogenic factor, inducing hypersprouting formation and abnormal growth in a LEC-specific manner. Mass spectrometry analysis revealed that vIRF3 interacted with histone deacetylase 5 (HDAC5), which is a signal-responsive regulator for vascular homeostasis. This interaction blocked the phosphorylation-dependent cytosolic translocation of HDAC5 and ultimately altered global gene expression in LECs but not in BECs. Consequently, vIRF3 robustly induced spindle morphology and hypersprouting formation of LECs but not BECs. Finally, KSHV infection led to the hypersprouting formation of LECs, whereas infection with a ΔvIRF3 mutant did not do so. Collectively, our data indicate that vIRF3 alters global gene expression and induces a hypersprouting formation in an HDAC5-binding-dependent and LEC-specific manner, ultimately contributing to KSHV-associated pathogenesis.

Oroxylin A inhibits Kaposi's sarcoma‐associated herpes virus (KSHV) vIL‐6–mediated lymphatic reprogramming of vascular endothelial cells through modulating PPARγ/Prox1 axis

“…As shown inFigure 5C, oroxylin A treatment significantly elevated the level of ubiquitinational Prox1 in the vIL-6expressing endothelial cells, which were pretreated with MG132, a specific inhibitor of the proteasome. In sum, these results reveal that interaction by PPARγ facilitates Prox1 to undergo ubiquitinational degradation.4 | DISCUSSIONLymphatic reprogramming plays a pivotal role in KS development [24][25][26]. In the present study, we successfully established a lymphatic-phenotype endothelial cell line by transduction of KSHV vIL-6 gene into the HUVECs.…”

“…Lymphatic reprogramming plays a pivotal role in KS development . In the present study, we successfully established a lymphatic‐phenotype endothelial cell line by transduction of KSHV vIL‐6 gene into the HUVECs.…”

Sirtuin 6 Attenuates Kaposi's Sarcoma-Associated Herpesvirus Reactivation by Suppressing Ori-Lyt Activity and Expression of RTA

“…No specific SIRT6 inhibitor (small compound) is available; the SIRT6-KSHV DNA might be an effective target for developing an interfering molecule for infection prevention or therapeutic purposes. Interestingly, a recent study found that the KSHV-encoded protein viral interferon regulatory factor 3, which interacts with HDAC5, contributes to KSHV-induced lymphangiogenesis, which is related to KSHV-caused malignancy (35). Therefore, studies on the relationship between HDAC/SIRT and KSHV might also result in an understanding of how KSHV causes cancer.…”

Novel functions of Kaposi’s sarcoma herpesvirus viral FLICE inhibitory protein

“…KSHV oncogenesis is, in part, attributed to genes expressed during latency. Viral FLICE inhibitory protein (vFLIP or K13), is a latently expressed gene that was originally identified as an inhibitor of apoptosis, due to the presence of tandem death effector domains 8,9 . vFLIP is a potent activator of NFκB signaling and this activity is dependent on interaction with IKKߛ 10-12 . vFLIP has also been shown to promote NFκB signaling through upregulation of IKKߝ and CADM1 and inhibition of the SAP18/HDAC1 complex resulting in activation of NFκB via acetylation of p65 [13][14][15] .…”