TY - JOUR
T1 - Human Cytomegalovirus UL7, miR-US5-1, and miR-UL112-3p Inactivation of FOXO3a Protects CD34+ Hematopoietic Progenitor Cells from Apoptosis
AU - Hancock, Meaghan H.
AU - Crawford, Lindsey B.
AU - Perez, Wilma
AU - Struthers, Hillary M.
AU - Mitchell, Jennifer
AU - Caposio, Patrizia
N1 - Publisher Copyright:
© 2021. Hancock et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. All Rights Reserved.
PY - 2020/12/11
Y1 - 2020/12/11
N2 - Human cytomegalovirus (HCMV) infection of myeloid lineage cells, such as CD341 hematopoietic progenitor cells (HPCs) or monocytes, results in the upregulation of antiapoptotic cellular proteins that protect the newly infected cells from programmed cell death. The mechanisms used by HCMV to regulate proapoptotic cellular proteins upon infection of CD341 HPCs have not been fully explored. Here, we show that HCMV utilizes pUL7, a secreted protein that signals through the FLT3 receptor, and miR-US5-1 and miR-UL112-3p to reduce the abundance and activity of the proapoptotic transcription factor FOXO3a at early times after infection of CD341 HPCs. Regulation of FOXO3a by pUL7, miR-US5-1, and miR-UL112 results in reduced expression of the proapoptotic BCL2L11 transcript and protection of CD341 HPCs from virus-induced apoptosis. These data highlight the importance of both viral proteins and microRNAs (miRNAs) in protecting CD341 HPCs from apoptosis at early times postinfection, allowing for the establishment of latency and maintenance of viral genome-containing cells. IMPORTANCE Human cytomegalovirus (HCMV) causes serious disease in immunocompromised individuals and is a significant problem during transplantation. The virus can establish a latent infection in CD341 hematopoietic progenitor cells (HPCs) and periodically reactivate to cause disease in the absence of an intact immune system. What viral gene products are required for successful establishment of latency is still not fully understood. Here, we show that both a viral protein and viral miRNAs are required to prevent apoptosis after infection of CD341 HPCs. HCMV pUL7 and miRNAs miR-US5-1 and miR-UL112-3p act to limit the expression and activation of the transcription factor FOXO3a, which in turn reduces expression of proapoptotic gene BCL2L11 and prevents virus-induced apoptosis in CD341 HPCs.
AB - Human cytomegalovirus (HCMV) infection of myeloid lineage cells, such as CD341 hematopoietic progenitor cells (HPCs) or monocytes, results in the upregulation of antiapoptotic cellular proteins that protect the newly infected cells from programmed cell death. The mechanisms used by HCMV to regulate proapoptotic cellular proteins upon infection of CD341 HPCs have not been fully explored. Here, we show that HCMV utilizes pUL7, a secreted protein that signals through the FLT3 receptor, and miR-US5-1 and miR-UL112-3p to reduce the abundance and activity of the proapoptotic transcription factor FOXO3a at early times after infection of CD341 HPCs. Regulation of FOXO3a by pUL7, miR-US5-1, and miR-UL112 results in reduced expression of the proapoptotic BCL2L11 transcript and protection of CD341 HPCs from virus-induced apoptosis. These data highlight the importance of both viral proteins and microRNAs (miRNAs) in protecting CD341 HPCs from apoptosis at early times postinfection, allowing for the establishment of latency and maintenance of viral genome-containing cells. IMPORTANCE Human cytomegalovirus (HCMV) causes serious disease in immunocompromised individuals and is a significant problem during transplantation. The virus can establish a latent infection in CD341 hematopoietic progenitor cells (HPCs) and periodically reactivate to cause disease in the absence of an intact immune system. What viral gene products are required for successful establishment of latency is still not fully understood. Here, we show that both a viral protein and viral miRNAs are required to prevent apoptosis after infection of CD341 HPCs. HCMV pUL7 and miRNAs miR-US5-1 and miR-UL112-3p act to limit the expression and activation of the transcription factor FOXO3a, which in turn reduces expression of proapoptotic gene BCL2L11 and prevents virus-induced apoptosis in CD341 HPCs.
KW - FOXO3a
KW - apoptosis
KW - hematopoietic progenitor cells
KW - human cytomegalovirus
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U2 - 10.1128/MSPHERE.00986-20
DO - 10.1128/MSPHERE.00986-20
M3 - Article
C2 - 33408225
AN - SCOPUS:85099966009
SN - 2379-5042
VL - 6
SP - 1
EP - 15
JO - mSphere
JF - mSphere
IS - 1
M1 - e00986-20
ER -