The KSHV K1 Protein Modulates AMPK Function to Enhance Cell Survival

PLoS Pathogens

Louise Giffin¹  Zhigang Zhang¹  Blossom Damania²  Prasana M. Bhende²  Penny M. Anders² 

[1] Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America;Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America

关键词: Kaposi's sarcoma-associated herpesvirus;    Cell metabolism;    Co-immunoprecipitation;    Cell viability testing;    MTS assay;    Nuclear membrane;    Cell membranes;    Immunoprecipitation;   

DOI  :  10.1371/journal.ppat.1005985

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY