Activation of the STAT6 transcription factor in Jurkat T-cells by the herpesvirus saimiri Tip protein

Kim, Yuri; Kwon, Eunjin; Jeon, Ju Hong; So, Insuk; Kim, In Gyu; Choi, Myung Sik; Kim, Ik Sang; Choi, Joong Kook; Jung, Jae U.; Cho, Nam Hyuk

doi:10.1099/vir.0.036087-0

Cited by 13 publications

(10 citation statements)

References 55 publications

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“…We could not exclude the possibility that cleaved STAT6 induced by LANA is not generated in the nucleus but is present in the cytoplasmic fraction due to protein shuttling. For example, recent reports have shown that STAT6 phosphorylation on Tyr 641 was induced by viral or parasitic infection independent of IL-4 [25–27]. However, the canonical STAT6 signaling induced by IL-4 is independent of STING or MAVS, which help viruses trigger STAT6 phosphorylation [28].…”

Section: Discussionmentioning

confidence: 99%

Nuclear Localization and Cleavage of STAT6 Is Induced by Kaposi’s Sarcoma-Associated Herpesvirus for Viral Latency

et al. 2017

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Emerging evidence implies that STAT6 plays an important role in both the adaptive and innate immune responses to virus infection. Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic γ-herpesvirus agent associated with several human malignancies, including Kaposi’s sarcoma (KS) and primary effusion lymphomas (PELs). Previously, we demonstrated that KSHV blocks IL-4-induced STAT6 phosphorylation and retains a basal IL-13/STAT6 constitutive activation for cell survival and proliferation. However, the mechanism by which KSHV regulates STAT6 remains largely unknown. Here, we found that KSHV-encoded LANA interacts with STAT6 and promotes nuclear localization of STAT6 independent of the tyrosine 641-phosphorylation state. Moreover, nuclear localization of STAT6 is also dramatically increased in KS tissue. The latent antigen LANA induces serine protease-mediated cleavage of STAT6 in the nucleus, where the cleaved STAT6 lacking transactivation domain functions as a dominant-negative regulator to repress transcription of Replication and Transcription Activator (RTA) and in turn shut off viral lytic replication. Blockade of STAT6 by small interference RNA dramatically enhances expression of RTA, and in turn reduces KSHV-infected endothelial cell growth and colony formation. Taken together, these results suggest that nuclear localization and cleavage of STAT6 is important for modulating the viral latency and pathogenesis of KSHV.

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Section: Discussionmentioning

confidence: 99%

Nuclear Localization and Cleavage of STAT6 Is Induced by Kaposi’s Sarcoma-Associated Herpesvirus for Viral Latency

et al. 2017

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“…It has been shown that ANXA2 can contribute to prostate cancer metastasis by interacting with the transcription factor STAT6 [25]. STAT6 can translocate to the cell nucleus where it acts as a transcription activator [26]. Interestingly, we found that in tissues with lymph node metastases, ANXA2 was mainly located in the nucleus (Fig.…”

Section: Discussionmentioning

confidence: 68%

Prognostic and diagnostic significance of annexin A2 in colorectal cancer

et al. 2013

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“…For instances, herpesvirus saimiri (HVS)-encoded Tip (tyrosine kinase-interacting protein) could interact with STAT6 and induce phosphorylation in T cells (22); SHP1 expression was selectively downregulated in human T-cell leukemia virus 1 (HTLV-1)-transformed T-cell lines, and Tax transactivates IL-13 overexpression (43,44). In addition, EBV Zta protein is able to induce the expression of IL-13 and promote the proliferation of EBV-infected B cells (45).…”

Section: Discussionmentioning

confidence: 99%

“…Mechanistically, STAT6 is constitutively activated in primary mediastinal large B-cell lymphomas due to amplification of JAK2 (13), while in hepatocellular carcinoma, gastric carcinoma, colorectal cancer, and hematological malignancies, STAT6 activation results from promoter hypermethylation and silencing of SHP1 or SOCS1 (17)(18)(19)(20). Interestingly, in virus-associated diseases, constitutive STAT6 activation occurs through different pathways (21)(22)(23). We and other colleagues recently found that in KSHV-associated cancers, IL-4-mediated STAT6 activation is tightly regulated by the virus in order to switch life cycles from latency to lytic replication (24,25).…”

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confidence: 99%

Constitutive Activation of Interleukin-13/STAT6 Contributes to Kaposi's Sarcoma-Associated Herpesvirus-Related Primary Effusion Lymphoma Cell Proliferation and Survival

Wang

Zhu

Wei

et al. 2015

J Virol

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Activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway has been associated with numerous human malignancies, including primary effusion lymphomas (PELs). PEL, a cancerous proliferation of B cells, is caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Previously we identified constitutive phosphorylation of STAT6 on tyrosine 641 (p-STAT6C ) in PEL cell lines BC3 and BCBL1; however, the molecular mechanism leading to this activation remains unclear. Here we demonstrate that STAT6 activation tightly correlates with interleukin-13 (IL-13) secretion, JAK1/2 tyrosine phosphorylation, and reduced expression of SHP1 due to KSHV infection. Moreover, p-STAT6 C and reduction of SHP1 were also observed in KS patient tissue. Notably, blockade of IL-13 by antibody neutralization dramatically inhibits PEL cell proliferation and survival. Taken together, these results suggest that IL-13/STAT6 signaling is modulated by KSHV to promote host cell proliferation and viral pathogenesis. IMPORTANCESTAT6 is a member of signal transducer and activator of transcription (STAT) family, whose activation is linked to KSHV-associated cancers. The mechanism through which STAT6 is modulated by KSHV remains unclear. In this study, we demonstrated that constitutive activation of STAT6 in KSHV-associated PEL cells results from interleukin-13 (IL-13) secretion and reduced expression of SHP1. Importantly, we also found that depletion of IL-13 reduces PEL cell growth and survival. This discovery provides new insight that IL-13/STAT6 plays an essential role in KSHV pathogenesis. Cytokines play a critical role in many viral infections. Viruses not only manipulate host cytokine production to favor virus survival, replication, and infection but also help virus-infected cells to modulate the host immune response, which potentially results in the development of viral persistent infection, pathogenesis, or tumorigenesis (1). Kaposi's sarcoma-associated herpesvirus (KSHV), also named human herpesvirus 8 (HHV-8), is an oncogenic gammaherpesvirus that associates with several aggressive malignancies, including AIDS-related Kaposi's sarcoma (KS) (2), primary effusion lymphoma (PEL) (3), and multicentric Castleman's disease (MCD) (4). Increasing evidence has suggested that KSHV also deregulates an array of host cytokines, including interleukin-6 (IL-6), IL-8, and IL-1␣, thereby inducing cell proliferation and malignant transformation (5-8).Signal transducer and activator of transcription (STAT) proteins are a family of cytoplasmic transcription factors involved in cytokine signal transduction. STAT6 is a key member of the STAT family, whose role in the biology of cancer and immune cells has been firmly established (9, 10). STAT6 is activated by cytokine IL-4 or IL-13, via a common receptor chain, namely, IL-4R␣. Upon interleukin binding, IL-4R␣ dimerizes with IL-4R␥ or IL-13R␣1 to form type I or type II IL-4R receptor, respectively. The dimerized receptor recruits and activates phosphorylatio...

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Activation of the STAT6 transcription factor in Jurkat T-cells by the herpesvirus saimiri Tip protein

Cited by 13 publications

References 55 publications

Nuclear Localization and Cleavage of STAT6 Is Induced by Kaposi’s Sarcoma-Associated Herpesvirus for Viral Latency

Nuclear Localization and Cleavage of STAT6 Is Induced by Kaposi’s Sarcoma-Associated Herpesvirus for Viral Latency

Prognostic and diagnostic significance of annexin A2 in colorectal cancer

Constitutive Activation of Interleukin-13/STAT6 Contributes to Kaposi's Sarcoma-Associated Herpesvirus-Related Primary Effusion Lymphoma Cell Proliferation and Survival

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