RNF213 modulates γ-herpesvirus infection and reactivation via targeting the viral Replication and Transcription Activator

Author:

Tian Huabin1,Yu Kuai12,He Liang12ORCID,Xu Hongtao1,Han Chuanhui1,Zhang Xiaolin1,Wang Xinlu1,Zhang Xuyuan1,Zhang Liguo1,Gao Guangxia123,Deng Hongyu123ORCID

Affiliation:

1. CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P. R. China

2. University of the Chinese Academy of Sciences, Beijing 100049, P. R. China

3. CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P. R. China

Abstract

Interferons (IFNs) and the products of interferon-stimulated genes (ISGs) play crucial roles in host defense against virus infections. Although many ISGs have been characterized with respect to their antiviral activity, their target specificities and mechanisms of action remain largely unknown. Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus that is linked to several human malignancies. Here, we used the genetically and biologically related virus, murine gammaherpesvirus 68 (MHV-68) and screened for ISGs with anti-gammaherpesvirus activities. We found that overexpression of RNF213 dramatically inhibited MHV-68 infection, whereas knockdown of endogenous RNF213 significantly promoted MHV-68 proliferation. Importantly, RNF213 also inhibited KSHV de novo infection, and depletion of RNF213 in the latently KSHV-infected iSLK-219 cell line significantly enhanced lytic reactivation. Mechanistically, we demonstrated that RNF213 targeted the Replication and Transcription Activator (RTA) of both KSHV and MHV-68, and promoted the degradation of RTA protein through the proteasome-dependent pathway. RNF213 directly interacted with RTA and functioned as an E3 ligase to ubiquitinate RTA via K48 linkage. Taken together, we conclude that RNF213 serves as an E3 ligase and inhibits the de novo infection and lytic reactivation of gammaherpesviruses by degrading RTA through the ubiquitin–proteasome pathway.

Funder

Natural Science Foundation of Beijing Municipality

National Natural Science Foundation of China

Chinese Academy of Sciences the Strategic Priority Research Program

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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