KSHV LANA inhibits TGF-β signaling through epigenetic silencing of the TGF-β type II receptor

Abstract

IntroductionKaposi sarcoma herpesvirus (KSHV) is associated with the pathogenesis of primary effusion lymphoma (PEL), Kaposi sarcoma (KS), and some forms of multicentric Castleman disease (MCD). [1][2][3] Its genome contains an extensive number of pirated cellular homologs involved in subverting critical cellular regulatory processes. 4,5 As a member of the ␥-herpesvirus family, KSHV is characterized by a prolonged latency during which only a subset of its genes are expressed. These latently expressed gene products play important roles in immune evasion, cell proliferation, and inhibition of apoptosis.One of these latently expressed proteins, latency-associated nuclear antigen (LANA), is involved in several cellular processes. It is considered an oncogenic protein because of its ability to dysregulate tumor suppressor pathways associated with p53 and pRb and to transform primary rat embryo fibroblasts in cooperation with the cellular oncogene H-ras. 6,7 Its association with GSK-3␤, an important modulator of the Wnt signaling pathway, leads to accumulation of ␤-catenin and subsequent up-regulation of Tcf/Lefregulated genes. 8 LANA inhibits expression of the reactivation transcriptional activator (RTA/Lyta), which is critical for the switch from latency to lytic reactivation. 9,10 It tethers the viral episome to host chromatin during mitosis, ensuring KSHV DNA gets replicated and episomes are not lost during cellular division. 11-14 LANA also regulates viral as well as cellular gene expression. [6][7][8][15][16][17] Although some of the changes mediated by LANA occur indirectly via activation of ␤-catenin and E2F target genes, direct binding of LANA to DNA also results in transcriptional repression. 18,19 Interactions with corepressors mSin3, SAP30, and CIR, the methyl CpG-binding protein MeCP2, and the histone methyltransferase SUV39H1 are consistent with a direct role for LANA in transcriptional repression. 14,20,21 LANA has been shown to inhibit in vitro histone acetyltransferase activity of CREB-binding protein (CBP) and, more recently, to associate with Dnmt3a, a DNA methyltransferase involved in de novo DNA methylation, supporting a role for LANA in epigenetic gene regulation. 16,22 Transforming growth factor-beta (TGF-␤) is a multifunctional cytokine involved in diverse biologic processes, which include embryonic development, regulation of cell growth, differentiation, hematopoiesis, angiogenesis, immune function, and apoptosis (reviewed by Roberts and Sporn 23 and Massague 24 ). There are 3 isoforms of TGF-␤, each of which binds to the same heterotetrameric complex of type I (T␤RI) and type II (T␤RII) serine/ threonine kinase receptors. Initially, TGF-␤ binds to T␤RII, which leads to the recruitment and activation of T␤RI. Receptor-activated Smads (R-Smads), Smad2 and Smad3, are then phosphorylated by T␤RI and translocate into the nucleus in a complex with Smad4. In the nucleus, the Smad complex binds its cognate binding site as well as several transcription factors, transcriptional activators, or transcri...

KSHV Regulation of Fibulin-2 in Kaposi's Sarcoma

“…TGF-␤ is known to stimulate fibulin-5 expression in endothelial cells, 20 and recently, Di Bartolo et al, 2008, showed that KSHV LANA inhibits TGF-␤ signaling through epigenetic silencing of the TGF-␤ type II receptor. 35 They demonstrated that this pathway is blocked in PEL cells via downregulation of the TGF-␤ type II receptor.…”

Viral epigenomes in human tumorigenesis

“…All of them are linked to viral maintenance and to the perturbation of the host immune response (Dourmishev et al, 2003;zur Hausen, 2006;Areste´and Blackbourn, 2009). In particular, several of these proteins (LANA, v-cyclinD, vFLIP and kaposin) can affect the main tumorigenic pathways involved in regulating important tumor suppressors and oncogenic genes in mammals (Godden-Kent et al, 1997;Friborg et al, 1999;Radkov et al, 2000;Fujimuro et al, 2003;Guasparri et al, 2004;McCormick and Ganem, 2005;Bubman et al, 2007;Di Bartolo et al, 2008).…”

“…LANA is unmethylated (Chen et al, 2001) and is known to be associated with histone modifications and subsequent gene expression alterations in host and viral genes that contribute to viral oncogenesis (Sakakibara et al, 2004;Lu et al, 2006;Stuber et al, 2007). It has also been shown that the recruitment of a de novo methyltransferase (DNMT3b) causes downregulation of genes such as cadherin 13 and TGF-b by promoter methylation (Shamay et al, 2006;Di Bartolo et al, 2008).…”

How virus persistence can initiate the tumorigenesis process

“…These cells develop virus induced chromosome damage and can undergo abnormal mitosis (Table 2), both in vitro and [64] E6, E7 [66,67] Naturally occurring pre-S mutants [68] --EBNA-3C v-CYC [65] LMP-1 [63] Lytic proteins BZLF-1 [69] -E1, E2 [71,72] HBx [73,74] Core Tax [76,77] BGLF-5 [70] NS3 [23,62] NS5 [75] EBV: Epstein-Barr virus; HHV-8: Human herpesvirus 8, also named Kaposi sarcoma virus; HPV: Human papillomavirus; HBV: Hepatatis B virus; HCV: Hepatitis C virus; HTLV-1: Human T-cell leukemia virus 1. EBNA-3A, EBNA-3C [78] LANA-1 [81] E6 [83] HBx [85,86] Core [87] Tax [88] LMP-1 [79] microRNA [82] E7 [84] LMP-2 [80] EBV: Epstein-Barr virus; HHV-8: Human herpesvirus 8, also named Kaposi sarcoma virus; HPV: Human papillomavirus; HBV: Hepatatis B virus; HCV: Hepatitis C virus; HTLV-1: Human T-cell leukemia virus 1.…”