MORC3 restricts human cytomegalovirus infection by suppressing the major immediate-early promoter activity.
Xue-Hui MaYong-Xuan YaoXian-Zhang WangYue-Peng ZhouSheng-Nan HuangDong LiMeng-Jie MeiJing-Peng WuYu-Ting PanShuang ChengXuan JiangJin-Yan SunWen-Bo ZengSitang GongHan ChengMin-Hua LuoBo YangPublished in: Journal of medical virology (2022)
During the long coevolution of human cytomegalovirus (HCMV) and humans, the host has formed a defense system of multiple layers to eradicate the invader, and the virus has developed various strategies to evade host surveillance programs. The intrinsic immunity primarily orchestrated by promyelocytic leukemia (PML) nuclear bodies (PML-NBs) represents the first line of defense against HCMV infection. Here, we demonstrate that microrchidia family CW-type zinc finger 3 (MORC3), a PML-NBs component, is a restriction factor targeting HCMV infection. We show that depletion of MORC3 through knockdown by RNA interference or knockout by CRISPR-Cas9 augmented immediate-early protein 1 (IE1) gene expression and subsequent viral replication, and overexpressing MORC3 inhibited HCMV replication by suppressing IE1 gene expression. To relief the restriction, HCMV induces transient reduction of MORC3 protein level via the ubiquitin-proteasome pathway during the immediate-early to early stage. However, MORC3 transcription is upregulated, and the protein level recovers in the late stages. Further analyses with temporal-controlled MORC3 expression and the major immediate-early promoter (MIEP)-based reporters show that MORC3 suppresses MIEP activity and consequent IE1 expression with the assistance of PML. Taken together, our data reveal that HCMV enforces temporary loss of MORC3 to evade its repression against the initiation of immediate-early gene expression.
Keyphrases
- gene expression
- dna methylation
- early stage
- crispr cas
- poor prognosis
- endothelial cells
- binding protein
- public health
- transcription factor
- squamous cell carcinoma
- sars cov
- small molecule
- radiation therapy
- acute myeloid leukemia
- protein protein
- epstein barr virus
- signaling pathway
- lymph node
- artificial intelligence
- long non coding rna
- single cell
- cancer therapy
- brain injury
- induced pluripotent stem cells