STAT6 degradation and ubiquitylated TRIML2 are essential for activation of human oncogenic herpesvirus
Authors: Yuyan Wang
Fang Wei
Zhenghong Yuan
Feng Gu
Caixia Zhu
Erle Robertson
Qiliang Cai
Wenjia Xu
Cankun Cai
Chong Wang
Qing Zhu
Zhikang Qian
Ling Ding
Journal: PLoS Pathogens (2018)
Discipline: MICROBIOLOGY
Keywords: STAT6; herpesvirus; lytic replication; Kaposi's sarcoma-associated herpesvirus (KSHV); RTA
Affiliations: MOE& MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, P. R. China., ShengYushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P. R. China., 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., 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. 

Retracted: No

PubPeer comments:
 Figure 5B. Much more similar than you would expect. https: imgur.com wzP4gxz , 
 Penultimate author appears to be on the editorial board of this journal: https: journals.plos.org plospathogens s editorial-board , 
 1 June 2022 correction. https: journals.plos.org plospathogens article?id=10.1371 journal.ppat.1010579 The Fig 5B K6-STAT6-Ub (HA) panel is incorrect; instead of the correct K6 panel, an image of the WT results at a shorter exposure time was used inadvertently. Fig 5 has been updated below to show the correct K6 panel. The underlying image data for the blots presented in Fig 5 are provided in the S1 File below. The Fig 7A iSLK-KSHV GAPDH panel is incorrect, and Fig 7 has been updated to present the correct iSLK-KSHV GAPDH panel. The underlying image data for the blots presented in Fig 7 and the underlying individual level data presented in Fig 7E are provided in the S1 and S2 Files below. In addition to the errors above, the BC3 STAT6, BCBL1 STAT3, and BC3 GAPDH panels of Fig 1A have not been prepared in line with best practice guidelines for image preparation. These panels have been replaced in the updated Fig 1 below to represent the obtained results more accurately. The underlying image data for the blots presented in Fig 1 are provided in the S1 File below. The individual level data underlying the results presented in Fig 1D, 1E, 1F and 1G are provided in the S3u2013S6 Files below respectively. Furthermore, the authors would like to clarify that the similarities between the Fig 1A BCBL1 STAT6 panel and the Fig 4B BCBL1 STAT6 panel, as well as the similarities between the Fig 1A BCBL1 GAPDH panel, Fig 4B BCBL1 GAPDH panel, and the Fig 7B BCBL1 GAPDH panel are due to these panels being used to represent results obtained from the same experiments. The underlying image data underlying the results presented in Figs 1, 4 and 3 are provided in the S1 File below. Reference 1.Gu F, Wang C, Wei F, Wang Y, Zhu Q, Ding L, et al. (2018) STAT6 degradation and ubiquitylated TRIML2 are essential for activation of human oncogenic herpesvirus. PLoS Pathog 14(12): e1007416. https: doi.org 10.1371 journal.ppat.1007416 , 
 https: retractionwatch.com 2022 06 15 extensive-correction-adds-to-five-flagged-papers-for-upenn-professor ,