Abstract
The presumed DNA helicase encoded by ORF44 of Kaposi’s sarcoma-associated herpesvirus (KSHV) plays a crucial role in unwinding viral double-stranded DNA and initiating DNA replication during lytic reactivation. However, the regulatory mechanism of KSHV ORF44 has not been fully elucidated. In a previous study, we identified that N-Myc downstream regulated gene 1 (NDRG1), a host scaffold protein, facilitates viral genome replication by interacting with proliferating cell nuclear antigen (PCNA) and the latent viral protein latency-associated nuclear antigen (LANA) during viral latency. In the present study, we further demonstrated that NDRG1 can interact with KSHV ORF44 during viral lytic replication. We also found that the mRNA and protein levels of NDRG1 were significantly increased by KSHV ORF50-encoded replication and transcription activator (RTA). Remarkably, knockdown of NDRG1 greatly decreased the protein level of ORF44 and impaired viral lytic replication. Interestingly, NDRG1 enhanced the stability of ORF44 and inhibited its ubiquitin-proteasome-mediated degradation by reducing the polyubiquitination of the lysine residues at positions 79 and 368 in ORF44. In summary, NDRG1 is a novel binding partner of ORF44 and facilitates viral lytic replication by maintaining the stability of ORF44. This study provides new insight into the mechanisms underlying KSHV lytic replication.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV), referred to as human herpesvirus 8 and belonging to the human oncogenic γ herpesvirus family, is the etiological agent of several human malignancies, including the endothelial neoplasm Kaposi’s sarcoma (KS) and two B cell lymphoproliferative disorders: primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [1,2,3]
We report that the host protein N-Myc downstream regulated gene 1 (NDRG1), a novel ORF44 binding partner, is significantly upregulated during viral lytic replication and facilitates this process
We speculated that NDRG1 might interact with ORF44, thereby regulating KSHV lytic replication
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV), referred to as human herpesvirus 8 and belonging to the human oncogenic γ herpesvirus family, is the etiological agent of several human malignancies, including the endothelial neoplasm Kaposi’s sarcoma (KS) and two B cell lymphoproliferative disorders: primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [1,2,3]. The life cycle of KSHV comprises two different phases: latency and lytic replication [4,5]. Extensive evidence has indicated that both the latent and lytic phases of the KSHV life cycle contribute prominently to viral tumorigenesis [6,7]. As a strategy to escape host immune surveillance, KSHV establishes latency for lifelong persistent infection. The infectious progeny virus produced by viral lytic replication and constant infection of fresh cells are critical for viral tumorigenicity [17,18,19]. Exploring the molecular mechanisms of the viral lytic replication phase is crucial to elucidating viral pathogenesis and may identify potential therapeutic and prophylactic strategies for KSHV-related diseases
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