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Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon Antiviral Activity.

Abstract Interferon-α (IFNα) signaling is essential for antiviral response via induction of IFN-stimulated genes (ISGs). Through a non-biased high-throughput RNAi screening of 711 known epigenetic modifiers in cellular models of IFNα-mediated inhibition of HBV replication, we identified methyltransferase SETD2 as a critical amplifier of IFNα-mediated antiviral immunity. Conditional knockout mice with hepatocyte-specific deletion of Setd2 exhibit enhanced HBV infection. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response. In addition, SETD2 selectively catalyzes the tri-methylation of H3K36 on promoters of some ISGs such as ISG15, leading to gene activation. Our study identifies STAT1 methylation on K525 catalyzed by the methyltransferase SETD2 as an essential signaling event for IFNα-dependent antiviral immunity and indicates potential of SETD2 in controlling viral infections.
PMID
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Authors

Mayor MeshTerms
Keywords

STAT1

antiviral immunity

interferon

lysine methylation

methyltransferase SETD2

Journal Title cell
Publication Year Start




PMID- 28753426
OWN - NLM
STAT- In-Process
DA  - 20170728
LR  - 20170728
IS  - 1097-4172 (Electronic)
IS  - 0092-8674 (Linking)
VI  - 170
IP  - 3
DP  - 2017 Jul 27
TI  - Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon 
      Antiviral Activity.
PG  - 492-506.e14
LID - S0092-8674(17)30761-4 [pii]
LID - 10.1016/j.cell.2017.06.042 [doi]
AB  - Interferon-alpha (IFNalpha) signaling is essential for antiviral response via
      induction of IFN-stimulated genes (ISGs). Through a non-biased high-throughput
      RNAi screening of 711 known epigenetic modifiers in cellular models of
      IFNalpha-mediated inhibition of HBV replication, we identified methyltransferase 
      SETD2 as a critical amplifier of IFNalpha-mediated antiviral immunity.
      Conditional knockout mice with hepatocyte-specific deletion of Setd2 exhibit
      enhanced HBV infection. Mechanistically, SETD2 directly mediates STAT1
      methylation on lysine 525 via its methyltransferase activity, which reinforces
      IFN-activated STAT1 phosphorylation and antiviral cellular response. In addition,
      SETD2 selectively catalyzes the tri-methylation of H3K36 on promoters of some
      ISGs such as ISG15, leading to gene activation. Our study identifies STAT1
      methylation on K525 catalyzed by the methyltransferase SETD2 as an essential
      signaling event for IFNalpha-dependent antiviral immunity and indicates potential
      of SETD2 in controlling viral infections.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Chen, Kun
AU  - Chen K
AD  - Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058,
      China; National Key Laboratory of Medical Immunology & Institute of Immunology,
      Second Military Medical University, Shanghai 200433, China.
FAU - Liu, Juan
AU  - Liu J
AD  - National Key Laboratory of Medical Immunology & Institute of Immunology, Second
      Military Medical University, Shanghai 200433, China.
FAU - Liu, Shuxun
AU  - Liu S
AD  - National Key Laboratory of Medical Immunology & Institute of Immunology, Second
      Military Medical University, Shanghai 200433, China.
FAU - Xia, Meng
AU  - Xia M
AD  - Department of Immunology & Center for Immunotherapy, Institute of Basic Medical
      Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences,
      Beijing 100005, China.
FAU - Zhang, Xiaomin
AU  - Zhang X
AD  - National Key Laboratory of Medical Immunology & Institute of Immunology, Second
      Military Medical University, Shanghai 200433, China.
FAU - Han, Dan
AU  - Han D
AD  - Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058,
      China.
FAU - Jiang, Yingming
AU  - Jiang Y
AD  - National Key Laboratory of Medical Immunology & Institute of Immunology, Second
      Military Medical University, Shanghai 200433, China.
FAU - Wang, Chunmei
AU  - Wang C
AD  - Department of Immunology & Center for Immunotherapy, Institute of Basic Medical
      Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences,
      Beijing 100005, China.
FAU - Cao, Xuetao
AU  - Cao X
AD  - Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058,
      China; National Key Laboratory of Medical Immunology & Institute of Immunology,
      Second Military Medical University, Shanghai 200433, China; Department of
      Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences,
      Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing
      100005, China. Electronic address: [email protected]
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
OTO - NOTNLM
OT  - STAT1
OT  - antiviral immunity
OT  - interferon
OT  - lysine methylation
OT  - methyltransferase SETD2
EDAT- 2017/07/29 06:00
MHDA- 2017/07/29 06:00
CRDT- 2017/07/29 06:00
PHST- 2017/01/29 [received]
PHST- 2017/05/04 [revised]
PHST- 2017/06/27 [accepted]
AID - S0092-8674(17)30761-4 [pii]
AID - 10.1016/j.cell.2017.06.042 [doi]
PST - ppublish
SO  - Cell. 2017 Jul 27;170(3):492-506.e14. doi: 10.1016/j.cell.2017.06.042.