Novel role of bone morphogenetic protein 9 (BMP9) in innate host responses to HCMV infection

Herpesviruses modulate immune control to secure lifelong infection. The diverse mechanisms Human Cytomegalovirus (HCMV) employs in this regard can reveal unanticipated aspects of cellular signalling involved in antiviral immunity. Here, we describe a novel relationship between the transforming growth factor-beta (TGF-β) family cytokine bone morphogenetic protein 9 (BMP9) and HCMV infection. We identified cross-talk between BMP9-induced and type I interferon (IFN) receptor-mediated signaling, showing that BMP9 boosts the transcriptional response to and antiviral activity of IFNβ, and thereby enhances restriction of HCMV replication. We also show that BMP9 is secreted by human fibroblasts upon HCMV infection. However, HCMV infection impairs BMP9-induced enhancement of the response to IFNβ, indicating that this innate immune signalling role of BMP9 is actively targeted by HCMV. Indeed, we show that transmembrane proteins US18 and US20, which downregulate type I BMP receptors, are necessary and sufficient to cause inhibition of BMP9-mediated boosting of the antiviral response to IFNβ, so that HCMV lacking US18 and US20 is more sensitive to IFNβ. These results demonstrate that HCMV has a mutually antagonistic relationship with BMP9 and substantially extend the growing body of evidence that BMP signalling is an underappreciated modulator of innate immunity to viral infection.

[1]  M. Gale,et al.  RIG-I and MDA5 are modulated by bone morphogenetic protein (BMP6) and are essential for restricting Zika virus infection in human Sertoli cells , 2023, Frontiers in Microbiology.

[2]  G. Cheng,et al.  The battle between host and SARS-CoV-2: Innate immunity and viral evasion strategies , 2022, Molecular Therapy.

[3]  P. Griffiths,et al.  Pathogenesis of human cytomegalovirus in the immunocompromised host , 2021, Nature Reviews Microbiology.

[4]  Shicui Zhang,et al.  Bmp8a is an essential positive regulator of antiviral immunity in zebrafish , 2021, Communications biology.

[5]  A. Pichlmair,et al.  The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription , 2020, Microorganisms.

[6]  P. J. Kranzusch,et al.  Conserved strategies for pathogen evasion of cGAS–STING immunity , 2020, Current Opinion in Immunology.

[7]  Yaosheng Chen,et al.  Bone Morphogenetic Protein 15 Knockdown Inhibits Porcine Ovarian Follicular Development and Ovulation , 2019, Front. Cell Dev. Biol..

[8]  J. D. Etlinger,et al.  Role of SMURF1 ubiquitin ligase in BMP receptor trafficking and signaling. , 2019, Cellular signalling.

[9]  S. Paludan,et al.  The herpesviral antagonist m152 reveals differential activation of STING‐dependent IRF and NF‐κB signaling and STING's dual role during MCMV infection , 2019, The EMBO journal.

[10]  C. Webber,et al.  Antiviral activity of bone morphogenetic proteins and activins , 2018, Nature Microbiology.

[11]  S. Jonjić,et al.  The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription , 2017, PLoS pathogens.

[12]  Ming Yan,et al.  STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling , 2017, Nature Structural &Molecular Biology.

[13]  S. Gygi,et al.  Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation , 2017, eLife.

[14]  S. Dooley,et al.  BMP9 a possible alternative drug for the recently withdrawn BMP7? New perspectives for (re-)implementation by personalized medicine , 2016, Archives of Toxicology.

[15]  Anatoly Kiyatkin,et al.  The Dark Side of Cell Signaling: Positive Roles for Negative Regulators , 2016, Cell.

[16]  A. Luganini,et al.  Inactivation of the Human Cytomegalovirus US20 Gene Hampers Productive Viral Replication in Endothelial Cells , 2015, Journal of Virology.

[17]  M. Weekes,et al.  Two Novel Human Cytomegalovirus NK Cell Evasion Functions Target MICA for Lysosomal Degradation , 2014, PLoS pathogens.

[18]  G. Inman,et al.  BMP9 Is a Proliferative and Survival Factor for Human Hepatocellular Carcinoma Cells , 2013, PloS one.

[19]  真田 昌.  骨髄異形成症候群のgenome-wide analysis , 2013 .

[20]  Jianni Qi,et al.  Smurf1 Protein Negatively Regulates Interferon-γ Signaling through Promoting STAT1 Protein Ubiquitination and Degradation* , 2012, The Journal of Biological Chemistry.

[21]  L. David,et al.  BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain , 2012, Cellular and molecular life sciences : CMLS.

[22]  K. Clément,et al.  Activin A Plays a Critical Role in Proliferation and Differentiation of Human Adipose Progenitors , 2010, Diabetes.

[23]  K. Miyazono,et al.  BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo , 2010, Journal of Cell Science.

[24]  Gregory A. Smith,et al.  En passant mutagenesis: a two step markerless red recombination system. , 2010, Methods in molecular biology.

[25]  A. Bowie,et al.  Viral evasion and subversion of pattern-recognition receptor signalling , 2008, Nature Reviews Immunology.

[26]  K. Sampaio,et al.  Cloning and sequencing of a highly productive, endotheliotropic virus strain derived from human cytomegalovirus TB40/E. , 2008, The Journal of general virology.

[27]  L. David,et al.  Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. , 2007, Blood.

[28]  R. Kamijo,et al.  Purification and identification of a BMP-like factor from bovine serum. , 2006, Biochemical and biophysical research communications.

[29]  K. Shuai,et al.  UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity , 2006, The EMBO journal.

[30]  Allison L. Zajac,et al.  Genome-Wide Analysis Reveals a Highly Diverse CD8 T Cell Response to Murine Cytomegalovirus , 2006 .

[31]  Jeffrey L. Wrana,et al.  A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation , 1999, Nature.

[32]  E. Huang,et al.  Characterization of a structurally tricistronic gene of human cytomegalovirus composed of U(s)18, U(s)19, and U(s)20 , 1993, Journal of virology.

[33]  M. Ramsay,et al.  Outcome of confirmed symptomatic congenital cytomegalovirus infection. , 1991, Archives of disease in childhood.

[34]  W. Britt,et al.  A rapid microneutralization assay for the measurement of neutralizing antibody reactive with human cytomegalovirus. , 1989, Journal of virological methods.

[35]  N. Flournoy,et al.  Risk factors for cytomegalovirus infection after human marrow transplantation. , 1986, The Journal of infectious diseases.

[36]  J. Cohen,et al.  Cytomegalovirus Infection in the Normal Host , 1985, Medicine.

[37]  And,et al.  Characterization of a structurally tricistronic gene of human cytomegalovirus composed of U(s)18, U(s)19, and U(s)20 , 1993, Journal of virology.