Question

Many viruses that infect eukaryotic cells express genes that alter the regulation of host gene expression to promote viral replication. For example, herpes simplex virus- 1 (HSV-1) expresses a protein called ICP0, which is necessary for successful viral infection and replication within the host. Lutz et al. (2017. Viruses 9: 210 ) showed that ICP0 can act as a ubiquitin ligase and target the redundant transcriptional repressors ZEB1 and ZEB2, which leads to upregulation of the miR-183 cluster (a set of three miRNAs transcribed from the same locus). (a) What likely happens to ZEB1 and ZEB2 upon HSV-1 infection? (b) How may ICP0 expression in a host cell lead to upregulation of the miR-183 cluster? (c) Speculate on how miR-183 cluster upregulation may benefit the virus.

Short answer

Answer: Upon HSV-1 infection, ICP0 protein is expressed, which leads to the targeting and likely degradation of ZEB1 and ZEB2 due to its ubiquitin ligase activity. This removal of ZEB1 and ZEB2 allows for the upregulation of the miR-183 cluster as their repressive effect is no longer present. The upregulation of the miR-183 cluster may provide benefits to the virus by suppressing the host's immune response or promoting viral replication.

Step-by-step solution

(a) Consequences of HSV-1 Infection on ZEB1 and ZEB2

Upon HSV-1 infection, the virus expresses the ICP0 protein, which acts as a ubiquitin ligase. ICP0 has been shown to target the transcriptional repressors ZEB1 and ZEB2. When targeted by ubiquitin ligase, proteins get ubiquitinated, which is a process that usually leads to proteasomal degradation. As a result, it is likely that levels of ZEB1 and ZEB2 will decrease upon HSV-1 infection.

(b) ICP0 Role in Upregulating miR-183 Cluster

ICP0, by targeting and leading to the degradation of ZEB1 and ZEB2, removes the repression effect these proteins have on the miR-183 cluster. With ZEB1 and ZEB2 out of the picture, transcription of the miR-183 cluster can proceed, resulting in upregulation of the miR-183 cluster.

(c) Possible Advantages for the Virus from miR-183 Cluster Upregulation

Although the specific functions of the miR-183 cluster in the context of HSV-1 infection might not be well-established, it is possible that upregulation of these miRNAs could provide multiple benefits for the virus. For example, the miR-183 cluster could target cellular genes involved in host immunity, thereby suppressing the host's immune response to the virus. Alternatively, the miRNAs could regulate host genes involved in cell division and/or metabolism in ways that promote viral replication. Basically, upregulation of the miR-183 cluster could manipulate the host cell environment to create more favorable conditions for viral infection and replication.

Key concepts

Ubiquitin Ligase

Ubiquitin ligase is an essential component in cellular processes because it is responsible for tagging proteins for degradation. Imagine it as a postal worker whose job is to attach a stamp, called ubiquitin, onto packages (proteins) that need to be delivered to the recycling center of the cell, known as the proteasome.
This occurs in a procedure known as ubiquitination. The ubiquitin ligase ensures that unnecessary proteins, or those that could potentially harm the cell, are broken down and removed efficiently.

In the case of HSV-1 infection, the protein ICP0 acts as a ubiquitin ligase. ICP0 targets two proteins, ZEB1 and ZEB2, which are known transcriptional repressors. By marking them for degradation, ICP0 effectively drops off these proteins at the cell's recycling center, thereby decreasing their levels within the host cell. This mechanism is a clever tactic employed by the virus to control the host's cellular environment in a manner that favors viral replication.

miR-183 Cluster

The miR-183 cluster is a group of microRNAs originating from the same genetic locus. MicroRNAs (miRNAs) are small, non-coding RNA molecules that play key roles in the regulation of gene expression. They often act as silencers that bind to messenger RNAs (mRNAs) to prevent them from producing proteins.

Upon HSV-1 infection, the upregulation of miR-183 cluster is triggered due to the reduction of ZEB1 and ZEB2 caused by ICP0's ubiquitin ligase activity. These repressors usually suppress the activity of the miR-183 cluster. Therefore, when they are degraded, the miR-183 cluster is free to increase its expression.

• This upregulation allows the miR-183 cluster to exert its effects on the host cell, potentially altering key genes that regulate immunity, cell growth, or metabolism.

Understanding this regulation helps researchers grasp how viruses can strategically influence host cell functions to benefit their lifecycle.

Eukaryotic Host Infection

Infection of eukaryotic host cells by viruses such as HSV-1 involves a strategic manipulation of the host's cellular machinery to favor viral replication. Viruses have evolved multiple mechanisms to ensure their survival and propagation within host cells.

One of these tactics includes hijacking the host's gene expression pathways. The upregulation of the miR-183 cluster is part of this complex interplay. By degrading the transcriptional repressors ZEB1 and ZEB2, HSV-1 encourages an environment more conducive to its replication cycle.

• The virus may benefit from the miR-183 cluster by suppressing host immune responses or altering cellular pathways to support viral replication.
• This showcases the virus's ability to remodel the host cell's environment, creating conditions optimal for its replication and spread.

Understanding these tactics gives us insights into viral behavior and can guide the development of treatments targeting viral infections at the genetic level.