Antiviral activity of bone morphogenetic proteins and activins

被引：28

作者：

Eddowes, Lucya ^{[1
]}

Al-Hourani, Kinda ^{[1
]}

Ramamurthy, Narayan ^{[2
]}

Frankish, Jamie ^{[3
]}

Baddock, Hannah T. ^{[4
]}

Sandor, Cynthia ^{[5
]}

Ryan, John D. ^{[6
,7
]}

Fusco, Dahlene N. ^{[8
]}

Arezes, Joao ^{[1
]}

Giannoulatou, Eleni ^{[9
]}

Boninsegna, Sara ^{[2
,10
]}

Chevaliez, Stephane ^{[8
]}

Owens, Benjamin M. J. ^{[7
]}

Sun, Chia Chi ^{[11
,12
]}

Fabris, Paolo ^{[13
]}

Giordani, Maria Teresa ^{[13
]}

Martines, Diego ^{[10
]}

Vukicevic, Slobodan ^{[14
]}

Crowe, John ^{[6
]}

Lin, Herbert Y. ^{[11
,12
]}

Rehwinkel, Jan ^{[1
]}

McHugh, Peter J. ^{[4
]}

Binder, Marco ^{[3
]}

Babitt, Jodie L. ^{[11
,12
]}

Chung, Raymond T. ^{[8
]}

Lawless, Matthew W. ^{[15
]}

Armitage, Andrew E. ^{[1
]}

Webber, Caleb ^{[5
,16
]}

Klenerman, Paul ^{[2
,7
,17
]}

Drakesmith, Hal ^{[1
,18
]}

机构：

[1] Univ Oxford, John Radcliffe Hosp, MRC Weatherall Inst Mol Med, MRC Human Immunol Unit, Oxford, England

[2] Univ Oxford, Peter Medawar Bldg Pathogen Res, Oxford, England

[3] German Canc Res Ctr, Div Virus Associated Carcinogenesis F170, Res Grp Dynam Early Viral Infect & Innate Antivir, Heidelberg, Germany

[4] Univ Oxford, MRC Weatherall Inst Mol Med, Dept Oncol, Oxford, England

[5] Cardiff Univ, Dementia Res Inst, Cardiff, S Glam, Wales

[6] Mater Misericordiae Univ Hosp, Ctr Liver Dis, Dublin, Ireland

[7] John Radcliffe Hosp, Nuffield Dept Med, Expt Med Div, Translat Gastroenterol Unit, Oxford, England

[8] Harvard Med Sch, Massachusetts Gen Hosp, Gastrointestinal Unit, Liver Ctr,Dept Med, Boston, MA USA

[9] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Computat Biol Res Grp, Oxford, England

[10] Univ Padua, Dept Surg Gastroenterol Sci, Padua, Italy

[11] Harvard Med Sch, Massachusetts Gen Hosp, Nephrol Div, Program Anemia Signaling Res,Program Membrane Bio, Boston, MA USA

[12] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA USA

[13] San Bortolo Hosp, Dept Infect Dis & Trop Med, Vicenza, Italy

[14] Univ Zagreb, Ctr Translat & Clin Res, Sch Med, Zagreb, Croatia

[15] Mater Misericordiae Univ Hosp, UCD Sch Med & Med Sci, Expt Med, Dublin, Ireland

[16] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England

[17] John Radcliffe Hosp, NIHR Biomed Res Ctr, Oxford, England

[18] Oxford Biomed Res Ctr, Haematol Theme, Oxford, England

来源：

NATURE MICROBIOLOGY | 2019年 / 4卷 / 02期

基金：

英国惠康基金;

关键词：

B-VIRUS REPLICATION; HEPATITIS-B; HEPCIDIN EXPRESSION; INTERFERON; INFECTION; IDENTIFICATION; TRANSCRIPTION; BMP; INHIBITION; INDUCTION;

D O I：

10.1038/s41564-018-0301-9

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN.

引用

页码：339 / 351

页数：13

共 48 条

[1] Repression of bone morphogenetic protein and activin-inducible transcription by Evi-1 [J].

Alliston, T ;

Ko, TC ;

Cao, YN ;

Liang, YY ;

Feng, XH ;

Chang, CB ;

Derynck, R .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (25) :24227-24237

[2] Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression [J].

Babitt, JL ;

Huang, FW ;

Wrighting, DM ;

Xia, Y ;

Sidis, Y ;

Samad, TA ;

Campagna, JA ;

Chung, RT ;

Schneyer, AL ;

Woolf, CJ ;

Andrews, NC ;

Lin, HY .

NATURE GENETICS, 2006, 38 (05) :531-539

[3] Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling [J].

Besson-Fournier, Celine ;

Latour, Chloe ;

Kautz, Leon ;

Bertrand, Jessica ;

Ganz, Tomas ;

Roth, Marie-Paule ;

Coppin, Helene .

BLOOD, 2012, 120 (02) :431-439

[4] HIV-1 TAT represses transcription of the bone morphogenic protein receptor-2 in U937 monocytic cells [J].

Caldwell, RL ;

Gadipatti, R ;

Lane, KB ;

Shepherd, VL .

JOURNAL OF LEUKOCYTE BIOLOGY, 2006, 79 (01) :192-201

[5] MDA5 plays a critical role in interferon response during hepatitis C virus infection [J].

Cao, Xuezhi ;

Ding, Qiang ;

Lu, Jie ;

Tao, Wanyin ;

Huang, Bing ;

Zhao, Yanan ;

Niu, Junqi ;

Liu, Yong-Jun ;

Zhong, Jin .

JOURNAL OF HEPATOLOGY, 2015, 62 (04) :771-778

[6] An IRF-3-, IRF-5-, and IRF-7-Independent Pathway of Dengue Viral Resistance Utilizes IRF-1 to Stimulate Type I and II Interferon Responses [J].

Carlin, Aaron F. ;

Plummer, Emily M. ;

Vizcarra, Edward A. ;

Sheets, Nicholas ;

Joo, Yunichel ;

Tang, William ;

Day, Jeremy ;

Greenbaum, Jay ;

Glass, Christopher K. ;

Diamond, Michael S. ;

Shresta, Sujan .

CELL REPORTS, 2017, 21 (06) :1600-1612

[7] Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection [J].

Chen, LM ;

Borozan, I ;

Feld, J ;

Sun, J ;

Tannis, LL ;

Coltescu, C ;

Heathcote, J ;

Edwards, AM ;

McGilvray, ID .

GASTROENTEROLOGY, 2005, 128 (05) :1437-1444

[8] Use of the Pharmacological Inhibitor BX795 to Study the Regulation and Physiological Roles of TBK1 and IκB Kinase ε A DISTINCT UPSTREAM KINASE MEDIATES SER-172 PHOSPHORYLATION AND ACTIVATION [J].

Clark, Kristopher ;

Plater, Lorna ;

Peggie, Mark ;

Cohen, Philip .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (21) :14136-14146

[9] Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors [J].

Cuny, Gregory D. ;

Yu, Paul B. ;

Laha, Joydev K. ;

Xing, Xuechao ;

Liu, Ji-Feng ;

Lai, Carol S. ;

Deng, Donna Y. ;

Sachidanandan, Chetana ;

Bloch, Kenneth D. ;

Peterson, Randall T. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (15) :4388-4392

[10] The Membrane-Bound Transcription Factor CREB3L1 Is Activated in Response to Virus Infection to Inhibit Proliferation of Virus-Infected Cells [J].

Denard, Bray ;

Seemann, Joachim ;

Chen, Qiuyue ;

Gay, Austin ;

Huang, Hua ;

Chen, Yan ;

Ye, Jin .

CELL HOST & MICROBE, 2011, 10 (01) :65-74

← 1 2 3 4 5 →