Activation of PI3K/AKT and ERK MAPK signal pathways is required for the induction of lytic cycle replication of Kaposi's sarcoma-associated herpesvirus by herpes simplex virus type 1.

Abstract

BACKGROUND:

Kaposi's sarcoma-associated herpesvirus (KSHV) is causally linked to several acquired immunodeficiency syndrome-related malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and a subset of multicentric Castleman's disease. Regulation of viral lytic replication is critical to the initiation and progression of KS. Recently, we reported that herpes simplex virus type 1 (HSV-1) was an important cofactor that activated lytic cycle replication of KSHV. Here, we further investigated the possible signal pathways involved in HSV-1-induced reactivation of KSHV.

RESULTS:

By transfecting a series of dominant negative mutants and protein expressing constructs and using pharmacologic inhibitors, we found that either Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) or JAK1/STAT6 signaling failed to regulate HSV-1-induced KSHV replication. However, HSV-1 infection of BCBL-1 cells activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB, also called AKT) pathway and inactivated phosphatase and tensin homologue deleted on chromosome ten (PTEN) and glycogen synthase kinase-3β (GSK-3β). PTEN/PI3K/AKT/GSK-3β pathway was found to be involved in HSV-1-induced KSHV reactivation. Additionally, extracellular signal-regulated protein kinase (ERK) mitogen-activated protein kinase (MAPK) pathway also partially contributed to HSV-1-induced KSHV replication.

CONCLUSIONS:

HSV-1 infection stimulated PI3K/AKT and ERK MAPK signaling pathways that in turn contributed to KSHV reactivation, which provided further insights into the molecular mechanism controlling KSHV lytic replication, particularly in the context of HSV-1 and KSHV co-infection.

• Authors: Di Qin, Ninghan Feng, Weifei Fan, Xinting Ma, Qin Yan, Zhigang Lv, Yi Zeng, Jianzhong Zhu, Chun Lu
• Journal: BMC microbiology (BMC Microbiol) Vol. 11 Pg. 240 (Oct 27 2011) ISSN: 1471-2180 [Electronic] England
• PMID: 22032493 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• STAT3 Transcription Factor
• STAT3 protein, human
• STAT6 Transcription Factor
• STAT6 protein, human
• Phosphatidylinositol 3-Kinases
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinases
• Glycogen Synthase Kinase 3
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Cell Line
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Herpesvirus 1, Human (physiology)
• Herpesvirus 8, Human (physiology)
• Humans
• Mitogen-Activated Protein Kinases (metabolism)
• PTEN Phosphohydrolase (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• STAT3 Transcription Factor (metabolism)
• STAT6 Transcription Factor (metabolism)
• Signal Transduction
• Virus Replication