Kaposi Sarcoma Herpesvirus (KSHV) Latency-Associated Nuclear Antigen (LANA) recruits components of the MRN (Mre11-Rad50-NBS1) repair complex to modulate an innate immune signaling pathway and viral latency

PLoS Pathogens

Semra Kati¹  Sandra Koch¹  Magdalena Weidner-Glunde¹  Thomas F. Schulz¹  Susann Santag²  Giuseppe Mariggiò²  Jessica Rückert²  Guigen Zhang² 

[1] German Centre for Infection Research, Hannover-Braunschweig Site, Germany;Institute of Virology, Hannover Medical School, Hannover, Germany

关键词: Transcription factors;    Immunoblotting;    Co-immunoprecipitation;    Phosphorylation;    Small interfering RNAs;    DNA replication;    Plasmid construction;    Kaposi's sarcoma-associated herpesvirus;   

DOI  :  10.1371/journal.ppat.1006335

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Kaposi Sarcoma Herpesvirus (KSHV), a γ2-herpesvirus and class 1 carcinogen, is responsible for at least three human malignancies: Kaposi Sarcoma (KS), Primary Effusion Lymphoma (PEL) and Multicentric Castleman’s Disease (MCD). Its major nuclear latency protein, LANA, is indispensable for the maintenance and replication of latent viral DNA in infected cells. Although LANA is mainly a nuclear protein, cytoplasmic isoforms of LANA exist and can act as antagonists of the cytoplasmic DNA sensor, cGAS. Here, we show that cytosolic LANA also recruits members of the MRN (Mre11-Rad50-NBS1) repair complex in the cytosol and thereby inhibits their recently reported role in the sensing of cytoplasmic DNA and activation of the NF-κB pathway. Inhibition of NF-κB activation by cytoplasmic LANA is accompanied by increased lytic replication in KSHV-infected cells, suggesting that MRN-dependent NF-κB activation contributes to KSHV latency. Cytoplasmic LANA may therefore support the activation of KSHV lytic replication in part by counteracting the activation of NF-κB in response to cytoplasmic DNA. This would complement the recently described role of cytoplasmic LANA in blocking an interferon response triggered by cGAS and thereby promoting lytic reactivation. Our findings highlight a second point at which cytoplasmic LANA interferes with the innate immune response, as well as the importance of the recently discovered role of cytoplasmic MRN complex members as innate sensors of cytoplasmic DNA for the control of KSHV replication.

【 授权许可】

CC BY