Date Published: November 9, 2016
Publisher: Public Library of Science
Author(s): Penny M. Anders, Zhigang Zhang, Prasana M. Bhende, Louise Giffin, Blossom Damania, Thomas F. Schulz.
Kaposi’s sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS) as well as two lymphoproliferative diseases, primary effusion lymphoma and multicentric Castleman’s disease. KSHV encodes viral proteins, such as K1, that alter signaling pathways involved in cell survival. Expression of K1 has been reported to transform rodent fibroblasts, and K1 transgenic mice develop multiple tumors, suggesting that K1 has an important role in KSHV pathogenesis. We found that cells infected with a KSHV virus containing a WT K1 gene had a survival advantage under conditions of nutrient deprivation compared to cells infected with KSHV K1 mutant viruses. 5’ adenosine monophosphate-activated protein kinase (AMPK) responds to nutrient deprivation by maintaining energy homeostasis, and AMPK signaling has been shown to promote cell survival in various types of cancers. Under conditions of AMPK inhibition, we also observed that cells infected with KSHV containing a WT K1 gene had a survival advantage compared to KSHV K1 mutant virus infected cells. To explore the underpinnings of this phenotype, we identified K1-associated cellular proteins by tandem affinity purification and mass spectrometry. We found that the KSHV K1 protein associates with the gamma subunit of AMPK (AMPKγ1). We corroborated this finding by independently confirming that K1 co-immunoprecipitates with AMPKγ1. Co-immunoprecipitations of wild-type K1 (K1WT) or K1 domain mutants and AMPKγ1, revealed that the K1 N-terminus is important for the association between K1 and AMPKγ1. We propose that the KSHV K1 protein promotes cell survival via its association with AMPKγ1 following exposure to stress.
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of the endothelial cancer, Kaposi’s sarcoma (KS), and two B-cell lymphomas including primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [1–3]. KSHV-related malignancies primarily arise in immune-suppressed individuals including HIV-positive individuals and organ transplant recipients, although these cancers can also occur in the absence of immunosuppression. KS is a common cancer in some sub-Saharan African countries [4, 5].
Cell survival during KSHV infection is paramount to the establishment of life-long infection. Upon infection, KSHV primarily enters a latent state. During latency, KSHV expresses a limited number of proteins and microRNAs that enable it to successfully persist in the cell by avoiding the immune response and by promoting cell survival . When KSHV reactivates and enters the lytic stage, the cell must remain viable throughout viral replication and virion assembly so that infectious virions are generated. Cell death prior to completion of the lytic program would result in defective viral replication.