NDRG1 facilitates lytic replication of Kaposi’s sarcoma-associated herpesvirus by maintaining the stability of the KSHV helicase

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 previ...

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Bibliographic Details
Published in:PLoS pathogens 2021-06, Vol.17 (6), p.e1009645-e1009645
Main Authors: Dong, Lianghui, Dong, Jiazhen, Xiang, Min, Lei, Ping, Li, Zixian, Zhang, Fang, Sun, Xiaoyi, Niu, Danping, Bai, Lei, Lan, Ke
Format: Article
Language:English
Subjects:
Antibodies
Antigens
Biology and Life Sciences
Care and treatment
Deoxyribonucleic acid
Development and progression
DNA
DNA biosynthesis
DNA helicase
DNA replication
Epstein-Barr virus
Genetic aspects
Genetic regulation
Genomes
Health aspects
Helicases
Herpes
Herpesvirus diseases
Infections
Kaposi's sarcoma
Kaposis sarcoma
Latency
Latency-associated nuclear antigen
Lysine
Mass spectrometry
Medicine and Health Sciences
Myc protein
Plasmids
Proliferating cell nuclear antigen
Proteasomes
Protein expression
Proteins
Regulatory mechanisms (biology)
Replication
Research and Analysis Methods
Sarcoma
Scientific imaging
Stability
Transcription
Ubiquitin
Unwinding
Viral infections
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1009645