Modulation of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by MEK/ERK, JNK, and p38 Multiple Mitogen-Activated Protein Kinase Pathways during Primary Infection

Abstract

Infection by viruses alters signaling pathways as a result of cellular response to the infection and virus modulation of its environments. Viruses have evolved to depend on these altered cellular pathways for their successful infection and replication in the host cells. For example, modulation of mitogenactivated protein kinase (MAPK) pathways is essential for infection and replication of human immunodeficiency virus, hepatitis B virus, Epstein-Barr virus, and vaccinia virus (11,23,31,54), while modulation of the NF-B pathway facilitates infection and replication of Epstein-Barr virus, herpes simplex virus type 1, and influenza virus (22, 39, 44).Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, is a gammaherpesvirus associated with Kaposi's sarcoma (KS), primary effusion lymphoma, and multicentric Castleman's disease (14). The life cycle of KSHV has two phases. The latent phase, during which the virus is maintained as episomes and has restricted expression of latent genes, is essential for the development of KSHVinduced malignancies (41, 55). The lytic phase, during which the virus produces infectious virions for dissemination, modulates cellular signaling pathways through unrestricted expression of viral genes (14).KSHV infects a variety of cell types, including B cells, epithelial cells, keratinocytes, and endothelial cells. Although KSHV establishes latency in the majority of cell types following primary infection (29), we have found that efficient infection of human umbilical vein endothelial cells (HUVEC) is productive at the early stage of infection, producing large number of infectious virions preceded by strong expression of almost all viral lytic genes (19,53).KSHV entry into the host cells relies on the interaction of its envelope glycoprotein B (gB) with cellular receptor integrin ␣3␤1 (3). This specific ligand-receptor interaction activates focal adhesion kinase and the MEK-ERK1/2 MAPK pathway but not the JNK and p38 MAPK pathways (3, 38). The activation of MEK pathway is important for KSHV infection, since specific inhibitors of MEK pathway reduce KSHV infectivity and the expression of KSHV early transcripts without affecting virus binding (38,42). Consistently, overexpression of Raf, a component of MEK pathway, enhances KSHV infectivity at the postattachment stage (1). Recently, it has been shown that binding of KSHV virions to the cells is sufficient to activate the RTA (Orf50) promoter (32). These studies indicate a role for the MEK MAPK pathway in KSHV infection.We have recently shown that besides the MEK MAPK pathway, KSHV infection also activates JNK and p38 MAPK path-

Human herpesvirus 6B induces phosphorylation of p53 in its regulatory domain by a CK2- and p38-independent pathway

“…Disruption of EBV latency by BRLF1 is prevented by inhibitors of p38 or JNK (Adamson et al, 2000). Another human herpesvirus, Kaposi's sarcoma-associated herpesvirus (HHV-8), has been reported to activate the ERK, p38 and JNK MAP kinase pathways during primary infection (Naranatt et al, 2003;Xie et al, 2005), and the activation of these pathways is essential for HHV-8 infection (Pan et al, 2006). Inhibitors of all three MAP kinase pathways reduce HHV-8 infectivity by reducing lytic replication and, as a result, the yield of infectious virions (Pan et al, 2006).…”

“…Another human herpesvirus, Kaposi's sarcoma-associated herpesvirus (HHV-8), has been reported to activate the ERK, p38 and JNK MAP kinase pathways during primary infection (Naranatt et al, 2003;Xie et al, 2005), and the activation of these pathways is essential for HHV-8 infection (Pan et al, 2006). Inhibitors of all three MAP kinase pathways reduce HHV-8 infectivity by reducing lytic replication and, as a result, the yield of infectious virions (Pan et al, 2006). HHV-6B may also exploit the cellular MAP kinase pathways during infection, as the presence of an inhibitor of p38 reduced the level of the 116 kDa viral nuclear protein significantly, as detected by Western blotting.…”

Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases

“…There is also an increasing body of literature showing that JNK activation follows bacterial, fungal, prion, parasitic, or viral infections. Under these circumstances, JNK activation may influence important cellular consequences, such as alterations in gene expression (1,53,59,162,167,176,199,294,325,326,346), cell death (58,89,137,139,169,193,243,293), viral replication, persistent infection or progeny release (215,224,251,260), or altered cellular proliferation (178). The exact mechanism of JNK activation under each of these circumstances remains to be elucidated fully, although there may be involvement of Toll-like receptors, direct pathway modulation through interaction with upstream protein regulators, or the activation following an ER stress response (79,87,110,124,143,191,253,261,279,294,312).…”

Phosphorylation of Eukaryotic Translation Initiation Factor 4B (EIF4B) by Open Reading Frame 45/p90 Ribosomal S6 Kinase (ORF45/RSK) Signaling Axis Facilitates Protein Translation during Kaposi Sarcoma-associated Herpesvirus (KSHV) Lytic Replication

“…Kaposi sarcoma-associated herpesvirus (KSHV) is the etiological agent of endothelial neoplasm Kaposi sarcoma and two lymphoproliferative diseases, primary effusion lymphoma and multicentric Castleman disease. KSHV activates both MEK/ERK/RSK and AKT/mTOR/ S6K signaling pathways by multiple mechanisms (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). We recently found that the immediate early and tegument protein open reading frame 45 (ORF45) of KSHV interacts with RSK1 and RSK2 and causes sustained activation of RSK and ERK during lytic replication (17).…”