A BMPR2/YY1 signaling axis is required for human cytomegalovirus latency in undifferentiated myeloid cells

Poole, Emma, Carlan da Silva, Maria Cristina, Huang, Chris, Perera, Marianne, Jackson, Sarah, Groves, Ian J., Wills, Mark, Rana, Amer ORCID: https://orcid.org/0000-0002-2330-4643 and Sinclair, John (2021) A BMPR2/YY1 signaling axis is required for human cytomegalovirus latency in undifferentiated myeloid cells. mBIO, 12 (3). ISSN 2161-2129

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Human cytomegalovirus (HCMV) presents a major health burden in the immunocompromised and in stem cell transplant medicine. A lack of understanding about the mechanisms of HCMV latency in undifferentiated CD34+ stem cells, and how latency is broken for the virus to enter the lytic phase of its infective cycle, has hampered the development of essential therapeutics. Using a human induced pluri-potent stem cell (iPSC) model of HCMV latency and patient-derived myeloid cell pro-genitors, we demonstrate that bone morphogenetic protein receptor type 2 (BMPR2) is necessary for HCMV latency. In addition, we define a crucial role for the transcription factor Yin Yang 1 (YY1) in HCMV latency; high levels of YY1 are maintained in latently infected cells as a result of BMPR2 signaling through the SMAD4/SMAD6 axis. Activation of SMAD4/6, through BMPR2, inhibits TGFbeta receptor signaling, which leads to the degradation of YY1 via induction of a cellular microRNA (miRNA), hsa-miR-29a. Pharmacological targeting of BMPR2 in progenitor cells results in the degradation of YY1 and an inability to maintain latency and renders cells susceptible to T cell killing. These data argue that BMPR2 plays a role in HCMV latency and is a new potential therapeutic target for maintaining or disrupting HCMV latency in mye-loid progenitors. IMPORTANCE Understanding the mechanisms which regulate HCMV latency could allow therapeutic targeting of the latent virus reservoir from where virus reactivation can cause severe disease. We show that the BMPR2/TGFbeta receptor/YY1 signaling axis is crucial to maintain HCMV latency in undifferentiated cells and that pharmacological reduction of BMPR2 in latently infected cells leads to reactivation of the viral lytic transcription program, which renders the infected cell open to immune detection and clearance in infected individuals. Therefore, this work identifies key host-vi-rus interactions which regulate HCMV latent infection. It also demonstrates a potential new therapeutic approach to reduce HCMV reactivation-mediated disease by the treatment of donor stem cells/organs prior to transplantation, which could have a major impact in the transplant disease setting.

Item Type: Article
Additional Information: Funding Information: This work was funded by MRC grant MR/S00081X/1. We also thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Brazil, for providing the Research Fellowship Abroad (RFA) for Maria Cristina Carlan da Silva (grant 2018/19936-0). This research was funded by the British Heart Foundation (BHF; project grant PG/14/31/ 30786), the BHF IPAH cohort grant (SP/12/12/29836, principal investigator Nicholas Morrell), the Cambridge National Institute for Health Research Biomedical Research Centre, and the Dinosaur Trust (DT 001).
Uncontrolled Keywords: bmpr2,human cytomegalovirus,latency,stem cells,yy1,microbiology,virology,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2400/2404
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 01 Nov 2022 14:31
Last Modified: 06 Jun 2024 15:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/89463
DOI: 10.1128/mBio.00227-21


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