HCV and flaviviruses hijack cellular mechanisms for nuclear STAT2 degradation: Up-regulation of PDLIM2 suppresses the innate immune response

PLoS Pathogens
Michael A JoyceD Lorne Tyrrell

Abstract

Host encounters with viruses lead to an innate immune response that must be rapid and broadly targeted but also tightly regulated to avoid the detrimental effects of unregulated interferon expression. Viral stimulation of host negative regulatory mechanisms is an alternate method of suppressing the host innate immune response. We examined three key mediators of the innate immune response: NF-KB, STAT1 and STAT2 during HCV infection in order to investigate the paradoxical induction of an innate immune response by HCV despite a multitude of mechanisms combating the host response. During infection, we find that all three are repressed only in HCV infected cells but not in uninfected bystander cells, both in vivo in chimeric mouse livers and in cultured Huh7.5 cells after IFNα treatment. We show here that HCV and Flaviviruses suppress the innate immune response by upregulation of PDLIM2, independent of the host interferon response. We show PDLIM2 is an E3 ubiquitin ligase that also acts to stimulate nuclear degradation of STAT2. Interferon dependent relocalization of STAT1/2 to the nucleus leads to PDLIM2 ubiquitination of STAT2 but not STAT1 and the proteasome-dependent degradation of STAT2, predominantly within the nucleus. CRISP...Continue Reading

References

Sep 13, 2001·Stem Cells·D L Krebs, D J Hilton
Feb 26, 2003·Genes & Development·Oxana A MalakhovaDong-Er Zhang
Oct 27, 2004·Investigative Ophthalmology & Visual Science·Mario TorradoStanislav I Tomarev
Nov 27, 2004·Journal of Virology·Catherine B BiggerRobert E Lanford
Apr 13, 2005·Gastroenterology·Wenyu LinRaymond T Chung
May 3, 2005·Nature Reviews. Immunology·Leonidas C Platanias
Jun 21, 2005·Immunity·Takashi TanakaMichael J Grusby
Aug 19, 2005·Nature·Michael Gale, Eileen M Foy
Oct 6, 2005·Science's STKE : Signal Transduction Knowledge Environment·Daniela Ungureanu, Olli Silvennoinen
Nov 29, 2005·Trends in Immunology·Cynthia L Johnson, Michael Gale
Dec 31, 2005·Molecular and Cellular Biology·Keun Il KimDong-Er Zhang
Jan 18, 2006·Antiviral Research·Robert ThimmeFriedemann Weber
Feb 14, 2006·Cell Research·Rashu B SethZhijian J Chen
Mar 23, 2006·Annual Review of Immunology·Steven F Ziegler
Apr 6, 2006·Proceedings of the National Academy of Sciences of the United States of America·Yueh-Ming LooMichael Gale
Sep 19, 2006·Immunity·Anette H H van Boxel-DezaireGeorge R Stark
Jun 7, 2007·World Journal of Gastroenterology : WJG·Eliane F Meurs, Adrien Breiman
Mar 13, 2009·Journal of Virology·Joseph AshourAdolfo García-Sastre
May 15, 2009·Journal of Cellular and Molecular Medicine·Arun K MankanRoss McManus
Jul 1, 2009·Molecular and Cellular Biology·Magdalena Sarasin-FilipowiczMarkus H Heim
Aug 12, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Mustafa BenekliMeir Wetzler
Dec 19, 2009·Cytokine & Growth Factor Reviews·Sergei I Grivennikov, Michael Karin
Apr 12, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Zuzanna MakowskaMarkus H Heim
Jun 22, 2011·Proceedings of the National Academy of Sciences of the United States of America·Robert E LanfordStanley M Lemon
Oct 27, 2011·PLoS Pathogens·Natalie A CounihanBrett D Lindenbach
Apr 24, 2012·Immunity·George R Stark, James E Darnell

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Citations

Jul 24, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Mudan ZhangQinxue Hu
Oct 28, 2019·Viruses·Taryn M Serman, Michaela U Gack
May 1, 2021·Viruses·Erika Hay-McCullough, Juliet Morrison
Jul 10, 2021·Frontiers in Microbiology·Kul Raj RaiJi-Long Chen
Aug 21, 2021·Bioorganic & Medicinal Chemistry·Supreeti MahajanShailly Tomar
Aug 28, 2021·Journal of Clinical Immunology·Christopher James Arthur Duncan, Sophie Hambleton
Sep 28, 2021·Biochimica Et Biophysica Acta. Reviews on Cancer·Zong Sheng Guo, Zhaoxia Qu

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Methods Mentioned

BETA
nuclear translocation
ubiquitination
biopsies
confocal microscopy
proximity ligation
immunoprecipitation
PLA assay
proximity ligation assay
scraping
Infrared Imaging

Software Mentioned

Velocity
Metamorph
ImageJ

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