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.
Highlights
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]
We report that the degradation of STAT6 is induced and required for the lytic activation of human herpesviruses including oncogenic γ-herpesviruses (KSHV and EBV) and α/β
We observed that the protein level of STAT6 was downregulated when Kaposi’s sarcoma-associated herpesvirus (KSHV)-infected primary effusion lymphoma (PEL) cells were treated with tetradecanoyl phorbol acetate (TPA) and sodium butyrate
Summary
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]. 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. 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
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