KSHV-encoded vCyclin can modulate HIF1α levels to promote DNA replication in hypoxia.

Rajnish Kumar Singh,Zachary L Lamplugh,Paul Lieberman,Yan Yuan,Erle S Robertson,Dipayan Bose,Kunfeng Sun,Jianxin You,Yonggang Pei

doi:10.7554/elife.57436

Abstract

The cellular adaptive response to hypoxia, mediated by high HIF1α levels includes metabolic reprogramming, restricted DNA replication and cell division. In contrast to healthy cells, the genome of cancer cells, and Kaposi's sarcoma associated herpesvirus (KSHV) infected cells maintains replication in hypoxia. We show that KSHV infection, despite promoting expression of HIF1α in normoxia, can also restrict transcriptional activity, and promoted its degradation in hypoxia. KSHV-encoded vCyclin, expressed in hypoxia, mediated HIF1α cytosolic translocation, and its degradation through a non-canonical lysosomal pathway. Attenuation of HIF1α levels by vCyclin allowed cells to bypass the block to DNA replication and cell proliferation in hypoxia. These results demonstrated that KSHV utilizes a unique strategy to balance HIF1α levels to overcome replication arrest and induction of the oncogenic phenotype, which are dependent on the levels of oxygen in the microenvironment.

Highlights

Kaposi’s sarcoma associated herpesvirus is the causative agent of Kaposi’s sarcoma (KS) and is tightly linked to Primary effusion lymphoma (PEL) and Multicentric Castleman disease (MCD) (Boshoff and Weiss, 2002; Goncalves et al, 2017; Chang et al, 1994)
As HIF1a is one of the major effectors of hypoxia and mediates repression of DNA replication in hypoxic conditions, we investigated the protein levels of HIF1a in BJAB/BJAB-Kaposi’s sarcoma associated herpesvirus (KSHV) cells grown in hypoxia (Figure 1C)
The results clearly showed that expression of KSHV-encoded virus encoded homolog of human cyclin D (vCyclin) led to a drastic reduction in transcriptional activity of HIF1a based on the levels of its downstream targets, under both normoxic and hypoxic conditions (Figure 2B–D and Figure 2—figure supplement 1)

Summary

Introduction

Kaposi’s sarcoma associated herpesvirus is the causative agent of Kaposi’s sarcoma (KS) and is tightly linked to Primary effusion lymphoma (PEL) and Multicentric Castleman disease (MCD) (Boshoff and Weiss, 2002; Goncalves et al, 2017; Chang et al, 1994). Evidence suggests that there is a strong association between KSHV infection and KSHV-associated inflammatory cytokine syndrome (KICS) (Cantos et al, 2017; Polizzotto et al, 2012). Upon successful infection of host cells, the virus chooses to either enter a latent phase or continue toward lytic replication to generate more copies of infectious virions (Chandran, 2010; Nicol et al, 2016). The viral genome transitions through a series of epigenetic modifications that are predominantly at lysine residues on histones to minimize expression of the majority of encoded genes. A fraction of genes critical for latency is expressed (Uppal et al, 2015; Toth et al, 2010)

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