title: Nuclear Localization and Cleavage of STAT6 Is Induced by Kaposi's Sarcoma-Associated Herpesvirus for Viral Latency.
abstract: 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.
authors.affiliation: MOE& MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
authors.forename: Chong
authors.initials: C
authors.lastname: Wang
authors.affiliation: MOE& MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Zhu
authors.affiliation: ShengYushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P. R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wei
authors.affiliation: Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Gao
authors.affiliation: Medical Laboratory, Nanchang Hospital of Integrative Traditional Chinese and Western Medicine, Nanchang, P.R. China.
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.affiliation: MOE& MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Shanghai Public Health Clinical Center, Fudan University, Shanghai, P. R. China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Division of Hematology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, P. R. China.
authors.forename: Yin
authors.identifier: 0000-0001-7551-5509
authors.initials: Y
authors.lastname: Tong
authors.affiliation: MOE& MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, P. R. China.|Shanghai Public Health Clinical Center, Fudan University, Shanghai, P. R. China.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Xu
authors.affiliation: MOE& MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: MOE& MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, P. R. China.|Shanghai Public Health Clinical Center, Fudan University, Shanghai, P. R. China.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
authors.affiliation: MOE& MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
authors.forename: Qiliang
authors.initials: Q
authors.lastname: Cai
mesh_terms: D000956:Antigens, Viral / Q000276:immunology; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D054685:Lymphoma, Primary Effusion / Q000276:immunology / Q000821:virology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D034741:RNA, Small Interfering; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000276:immunology / Q000821:virology*; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D000956:Antigens, Viral; C578095:IL13 protein, human; D018793:Interleukin-13; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4