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Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of several AIDS-related cancers, including the endothelial cell (EC) neoplasm Kaposi's sarcoma (KS). KSHV-infected ECs secrete abundant host-derived pro-inflammatory molecules and angiogenic factors that contribute to tumorigenesis. The precise contributions of viral gene products to this secretory phenotype remain to be elucidated, but there is emerging evidence for post-transcriptional regulation. The Kaposin B (KapB) protein is thought to contribute to the secretory phenotype in infected cells by binding and activating the stress-responsive kinase MK2, thereby selectively blocking decay of AU-rich mRNAs (ARE-mRNAs) encoding pro-inflammatory cytokines and angiogenic factors. Processing bodies (PBs) are cytoplasmic ribonucleoprotein foci in which ARE-mRNAs normally undergo rapid 5′ to 3′ decay. Here, we demonstrate that PB dispersion is a feature of latent KSHV infection, which is dependent on kaposin protein expression. KapB is sufficient to disperse PBs, and KapB-mediated ARE-mRNA stabilization could be partially reversed by treatments that restore PBs. Using a combination of genetic and chemical approaches we provide evidence that KapB-mediated PB dispersion is dependent on activation of a non-canonical Rho-GTPase signaling axis involving MK2, hsp27, p115RhoGEF and RhoA. PB dispersion in latently infected cells is likewise dependent on p115RhoGEF. In addition to PB dispersion, KapB-mediated RhoA activation in primary ECs caused actin stress fiber formation, increased cell motility and angiogenesis; these effects were dependent on the activity of the RhoA substrate kinases ROCK1/2. By contrast, KapB-mediated PB dispersion occurred in a ROCK1/2-independent manner. Taken together, these observations position KapB as a key contributor to viral reprogramming of ECs, capable of eliciting many of the phenotypes characteristic of KS tumor cells, and strongly contributing to the post-transcriptional control of EC gene expression and secretion.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV), a.k.a. human herpesvirus-8 (HHV-8) is the infectious cause of Kaposi’s sarcoma (KS), the most common malignancy of untreated AIDS patients, and two rare lymphoproliferative disorders, multicentric Castleman’s disease (MCD) and primary effusion lymphoma (PEL) [1,2,3]
We investigated the ability of Kaposin B (KapB) to modulate the actin cytoskeleton in human umbilical vein endothelial cells (HUVECs)
Consistent with this, we observed that expression of either MK2-EE or hsp27DDD in HUVECs caused the formation of actin stress fibers (Figs. 1C, 1D)
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV), a.k.a. human herpesvirus-8 (HHV-8) is the infectious cause of Kaposi’s sarcoma (KS), the most common malignancy of untreated AIDS patients, and two rare lymphoproliferative disorders, multicentric Castleman’s disease (MCD) and primary effusion lymphoma (PEL) [1,2,3]. KSHV establishes persistent, life-long infection of its human host. The primary proliferative elements of KS lesions are latently infected endothelial cells (ECs) with an abnormal spindle-shaped morphology, commonly known as ‘spindle cells’. The viral episome persists in a reversible latent state and viral gene expression is limited to 6 consensus protein products (LANA, v-cyclin, v-FLIP, Kaposins A, B, and C) and 12 pre-miRNAs that are processed into at least 17 mature miRNAs (reviewed in [4], [5,6]). Spindle cells display actin cytoskeleton rearrangements, enhanced cell motility and an aberrant angiogenic phenotype (recently reviewed in [7,8]); all of these features can be recapitulated during in vitro infection of primary ECs [8,9,10,11]. Several KSHV latent gene products have been shown to contribute to these dramatic alterations in EC physiology (reviewed in [8]), but our understanding of their relative contribution to tumor-initiating events remains incomplete
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