STAT6 degradation and ubiquitylated TRIML2 are essential for activation of human oncogenic herpesvirus

Feng Gu; Chong Wang; Fang Wei; Yuyan Wang; Qing Zhu; Ling Ding; Wenjia Xu; Caixia Zhu; Cankun Cai; Zhikang Qian; Zhenghong Yuan; Erle Robertson; Qiliang Cai

doi:10.1371/journal.ppat.1007416

STAT6 degradation and ubiquitylated TRIML2 are essential for activation of human oncogenic herpesvirus

PLoS Pathog. 2018 Dec 10;14(12):e1007416. doi: 10.1371/journal.ppat.1007416. eCollection 2018 Dec.

Authors

Feng Gu¹, Chong Wang¹, Fang Wei², Yuyan Wang¹, Qing Zhu¹, Ling Ding¹, Wenjia Xu³, Caixia Zhu¹, Cankun Cai¹, Zhikang Qian³, Zhenghong Yuan¹, Erle Robertson⁴, Qiliang Cai¹

Affiliations

¹ MOE& MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
² ShengYushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P. R. China.
³ Unit of Herpesvirus and Molecular Virology, Key Laboratory of Molecular Virology &Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, P. R. China.
⁴ Department of Otorhinolaryngology-Head and Neck Surgery, Department of Microbiology, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America.

Abstract

Aberrations in STAT6-mediated signaling are linked to the development of multiple cancer types. Increasing evidence has shown that activation of human oncogenic herpesvirus lytic replication is crucial for viral tumorigenesis. However, the role of STAT6 in herpesvirus lytic replication remains elusive. Here, by using Kaposi's sarcoma-associated herpesvirus (KSHV) as a model, we revealed that RTA, the master regulator of lytic replication, interacts with STAT6 and promotes lysine 48 (K48) and K63-linked ubiquitylation of STAT6 for degradation via the proteasome and lysosome systems. Moreover, degradation of STAT6 is dramatically associated with the increased ubiquitylated form of tripartite motif family like 2 (TRIML2, a tumor suppressor) for prolonged cell survival and virion production, which is also commonly observed in lytic activation of Epstein-Barr virus, herpes simplex virus 1 and cytomegalovirus. These results suggest that degradation of STAT6 is important for the lytic activation of KSHV and as such, may be an attractive therapeutic target.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carrier Proteins / metabolism*
Cell Line
Herpesviridae Infections / metabolism*
Herpesvirus 8, Human / metabolism*
Humans
STAT6 Transcription Factor / metabolism*
Ubiquitination
Virus Activation / physiology*
Virus Latency / physiology

Substances

Carrier Proteins
STAT6 Transcription Factor
STAT6 protein, human
TRIML2 protein, human

Grants and funding

This work is supported by the National Natural Science Foundation of China (81672015, 81471930 to QC; 81772166 to FW, 81501739 to CZ), and the National Key Research and Development Program of China (2016YFC1200400 to QC). FW is a scholar of Pujiang Talents in Shanghai. QC is a scholar of New Century Excellent Talents in University of China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.