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Use of In vivo Imaging to Monitor the Progression of Experimental Mouse Cytomegalovirus Infection in Neonates
Published on: July 6, 2013
MORC3 restricts human cytomegalovirus infection by suppressing the major immediate-early promoter activity
Xue-Hui Ma1, Yong-Xuan Yao2, Xian-Zhang Wang1,3
1Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou, China.
Abstract:
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.
Insights
Human cytomegalovirus (HCMV) evades host immunity by reducing microrchidia family CW-type zinc finger 3 (MORC3) protein levels. This protein normally restricts viral replication by suppressing immediate-early gene expression.
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Human cytomegalovirus (HCMV) coevolves with humans, employing evasion strategies against host defenses.
- Intrinsic immunity, involving promyelocytic leukemia (PML) nuclear bodies (PML-NBs), is a primary defense against HCMV.
- Microrchidia family CW-type zinc finger 3 (MORC3) is a component of PML-NBs and acts as a restriction factor against HCMV.
Purpose of the Study:
- To investigate the role of MORC3 as a restriction factor in HCMV infection.
- To elucidate the mechanisms by which HCMV interacts with MORC3 during infection.
- To understand how HCMV evades MORC3-mediated restriction.
Main Methods:
- RNA interference (RNAi) for MORC3 knockdown.
- CRISPR-Cas9 gene editing for MORC3 knockout.
- Overexpression of MORC3.
- Analysis of immediate-early protein 1 (IE1) gene expression.
- Ubiquitin-proteasome pathway inhibition.
- Temporal-controlled MORC3 expression.
- Major immediate-early promoter (MIEP)-based reporter assays.
Main Results:
- Depletion of MORC3 enhanced IE1 gene expression and HCMV replication.
- Overexpression of MORC3 inhibited HCMV replication by suppressing IE1 expression.
- HCMV induces transient MORC3 protein reduction via the ubiquitin-proteasome pathway during early infection stages.
- MORC3 transcription and protein levels recover in later stages of infection.
- MORC3, with PML assistance, suppresses MIEP activity and IE1 expression.
Conclusions:
- MORC3 acts as a crucial restriction factor against HCMV by inhibiting immediate-early gene expression.
- HCMV employs a strategy of transient MORC3 downregulation to evade its antiviral activity during early infection.
- Understanding this interaction provides insights into HCMV pathogenesis and host-virus dynamics.
