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MORC3 represses the HCMV major immediate early promoter in myeloid cells in the absence of PML nuclear bodies.

Published version
Peer-reviewed

Repository DOI


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Authors

Champion, Anna 
Rowland, Alexandra 
Yee, Levia 
van den Boomen, Dick 
Reeves, Matthew 

Abstract

Human cytomegalovirus (HCMV) can undergo either a latent or a lytic infection in cells of the myeloid lineage. Whilst the molecular mechanisms which determine the outcome of infection are far from clear, it is well established that a key factor is the differential regulation of the major immediate early promoter (MIEP) responsible for driving lytic immediate early gene expression. Using a myelomonocytic cell line stably transduced with a GFP reporter under the control of the MIEP, which recapitulates MIEP regulation in the context of virus infection, we have used an unbiased CRISPR-Cas9 sub-genomic, epigenetic library screen to identify novel cellular factors involved in MIEP repression during establishment and maintenance of latency in myeloid cells. One such cellular factor identified was MORC3. Consistent with MORC3 being a robust repressor of the MIEP, we show that THP1 cells devoid of MORC3 fail to establish latency. We also show that MORC3 is induced during latent infection, recruited to the MIEP and forms MORC3 nuclear bodies (MORC3-NBs) which, interestingly, co-localize with viral genomes. Finally, we show that the latency-associated functions of MORC3 are regulated by the deSUMOylase activity of the viral latency-associated LUNA protein likely to prevent untimely HCMV reactivation.

Description

Publication status: Published

Keywords

MORC3, human cytomegalovirus, latency, Humans, Adenosine Triphosphatases, Cytomegalovirus, Cytomegalovirus Infections, DNA-Binding Proteins, Gene Expression Regulation, Viral, Myeloid Cells, Promyelocytic Leukemia Nuclear Bodies, Virus Latency

Journal Title

J Med Virol

Conference Name

Journal ISSN

0146-6615
1096-9071

Volume Title

95

Publisher

Wiley
Sponsorship
Medical Research Council (MR/S00081X/1)
Medical Research Council (MR/K021087/1)