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

Date Published: December 10, 2018

Publisher: Public Library of Science

Author(s): 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, Pinghui Feng.


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.

Partial Text

The signal transducer and activator of transcription (STAT) family are transcription factors that mediate the transmission of signals of numerous cytokines and growth factors from the cell membrane to the nucleus[1]. To date, there are at least seven identified STAT proteins, named STAT1, 2, 3, 4, 5a, 5b, and 6[2]. Dysregulation of STAT family members results in immune system disorder and cancer. STAT6, an important member of the STAT family, is a key responder to the stimulation of cytokines interleukin 4 (IL-4) and IL-13 in the differentiation of T helper 2 cells[3], and it is also involved in the antiviral immune response[4]. Typically, IL-4/13 binds and induces phosphorylation of the IL-4α receptor at the plasma membrane, which in turn recruits Janus kinase (JAK) and cytosolic STAT6 for phosphorylation[5]. The phosphorylation of STAT6 on tyrosine 641 (Y641) by JAK1 results in dimerization and translocation of STAT6 from the cytoplasm into the nucleus to activate downstream target genes, including IL-4 and CD23 via binding to the consensus DNA sequence TTC(N3/N4)GAA within the promoters[6]. Interestingly, other cytokines, including IL-3/15, IFNα, and PDGF, also activate STAT6 in different cell types[7–10]. In addition, recent studies have shown that primary virus infection can induce STAT6 activation in the endoplasmic reticulum independently of JAK, but it relies on a stimulator of interferon genes and TANK-binding kinase 1 for antiviral innate immunity[4]. This virus-induced STAT6 activation is commonly detected in all cell types, suggesting its fundamental role in the host immune defense against viral infections. Thus, STAT6 mediates the comprehensive regulation of immune signaling in response to both the stimulation of cytokines at the plasma membrane and viral infection in the endoplasmic reticulum.

The lytic phase of KSHV is critical for its oncogenesis and pathogenesis. Previous studies have reported that extracellular stimulation of IL-4 reactivates the KSHV lytic cycle[33], while KSHV not only blocks the IL-4-induced phosphorylation of STAT6 during latency[15], but also induces nuclear localization and cleavage of STAT6 to inhibit the transcription of RTA and blocks lytic replication[34]. In this study, we provided additional evidence for STAT6 as a key molecule that responds to lytic stimuli. Consistent with previous studies, we found that the degradation of STAT6 is induced upon KSHV reactivation. During reactivation of KSHV latently infected cells by stimuli, such as TPA and sodium butyrate, KSHV-encoded lytic antigen RTA not only blocks formation of the LANA-RBP-Jκ complex as previously reported [29,39], but also induces K48- and K63-linked ubiquitylation of STAT6 for degradation via the proteasome and lysosome. The fact that inhibition of STAT6 is sufficient to activate lytic cycle, indicates that it plays a critical role in controlling the KSHV life cycle. The interaction between STAT6 and RTA resulted in STAT6 degradation and increased the expression and ubiquitylated form of TRIML2, which in turn, prolongs host cell survival in lytic replication and enhances RTA expression to facilitate viral progeny production (Fig 8D). A similar phenomenon has also been observed in other human herpesviruses, including EBV, HCMV, and HSV1, when they undergo lytic replication, indicating that STAT6 degradation and TRIML2 ubiquitylation are required for reactivation of human herpesvirus from latency to the lytic cycle.




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