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3 recordsLinked to original sources
PubMed2026

The human cytomegalovirus vGPCR UL33 is essential for efficient lytic replication in epithelial cells.

UNLABELLED: Human cytomegalovirus (HCMV) is a β-herpesvirus that is ubiquitous in the human population. HCMV has the largest genome of the human herpesviruses and encodes an array of genes that affect pathogenesis in different cell types. Given the ability of HCMV to replicate in a range of cell types, investigators have begun to identify viral proteins required for cell type-specific replication. There are four proteins encoded by HCMV that are homologous to G protein-coupled receptors (GPCRs); these viral GPCRs (vGPCRs) are UL33, UL78, US27, and US28. In this study, we find that deletion of all four vGPCR genes severely attenuates HCMV replication in primary human salivary gland epithelial cells and ARPE-19 retinal epithelial cells, as evidenced by decreases in viral gene expression and virus production. Deletion of UL33 from the HCMV genome also results in a failure to efficiently replicate in epithelial cells, and this defect is manifested by decreased levels of viral gene expression and virus production. We find that, similar to US28, UL33 constitutively activates Gαq signaling to high levels in epithelial cells. We also find that UL33 transcription is more complicated than originally believed, and there is the potential for the virus to utilize various 5' UTRs to create novel UL33 proteins that are all capable of constitutive Gαq signaling. Taken together, these studies provide novel molecular and biochemical data regarding UL33 expression, subcellular localization, and signaling, and indicate that UL33 activity is essential for efficient HCMV replication in cells of epithelial origin. IMPORTANCE: Human cytomegalovirus (HCMV) replicates in a number of cell types and tissues in vivo, and the viral genes involved in cell type-specific replication are just beginning to be elucidated. The HCMV-encoded viral G protein-coupled receptors (vGPCRs) UL33, UL78, US27, and US28 are proving to play important roles in multiple aspects of HCMV replication, including the establishment and maintenance of latency. Here, we demonstrate that the HCMV vGPCRs and UL33, in particular, play an important role in driving lytic replication in cells of epithelial origin, including those derived from the salivary gland. This work expands on potential functions of the vGPCRs, will drive future studies to understand mechanistically how they affect tropism, and provides a new target for future therapeutics.

Gαq↗
PubMed2024

The Human Cytomegalovirus vGPCR UL33 is Essential for Efficient Lytic Replication in Epithelial Cells.

Human cytomegalovirus (HCMV) is a β-herpesvirus which is ubiquitous in the human population. HCMV has the largest genome of all known human herpesviruses, and thus encodes a large array of proteins that affect pathogenesis in different cell types. Given the large genome and the ability of HCMV to replicate in a range of cells, investigators have begun to identify viral proteins required for cell type-specific replication. There are four proteins encoded in the HCMV genome that are homologous to human G protein-coupled receptors (GPCRs); these viral-encoded GPCRs (vGPCRs) are UL33, UL78, US27, and US28. In the current study, we find that deletion of all four vGPCR genes from a clinical isolate of HCMV severely attenuates lytic replication in both primary human salivary gland epithelial cells, as well as ARPE-19 retinal epithelial cells as evidenced by significant decreases in immediate early gene expression and virus production. Deletion of UL33 from the HCMV genome also results in a failure to efficiently replicate in epithelial cells, and this defect is manifested by decreased levels of immediate early, early, and late gene expression, as well as reduced viral production. We find that similar to US28, UL33 constitutively activates Gαq-dependent PLC-β signaling to high levels in these epithelial cells. We also find that UL33 transcription is more complicated than originally believed, and there is the potential for the virus to utilize various 5' UTRs to create novel UL33 proteins that are all capable of constitutive Gαq signaling. Taken together, these studies suggest that UL33 driven signaling is important for lytic HCMV replication in cells of epithelial origin.

Journal Article↗
PubMed2025

Characterization of the Kaposi's sarcoma-associated herpesvirus terminase complex component ORF29.

Kaposi's sarcoma-associated herpesvirus (KSHV) belongs to the Gammaherpesvirinae subfamily. During the lytic phase of herpesviruses, viral capsids form in the host cell nucleus, and the replicated viral genome is packaged into these capsids. The herpesviral genome is replicated as a precursor head-to-tail concatemer consisting of tandemly repeated genomic units, each flanked by terminal repeats (TRs). The herpesvirus terminase complex packages a single genomic unit into a capsid by cleaving the TRs in the precursor genome. Although the terminase complexes of alpha- and beta-herpesviruses are well characterized, the KSHV terminase complex is poorly understood. KSHV ORF7, ORF67.5, and ORF29 are thought to be components of this complex. We previously reported that KSHV deficient in either ORF7 or ORF67.5 formed immature, soccer ball-like capsids and failed to cleave the TRs, resulting in decreased virion production. Moreover, ORF7 interacted with both ORF29 and ORF67.5; however, ORF29 and ORF67.5 did not interact with each other. Thus, although ORF7 and ORF67.5 are important for KSHV terminase function, the function of ORF29 remains largely unknown. In this study, we constructed an ORF29-deficient KSHV and analyzed its virological properties. ORF29 was found to be essential for virion production and TR cleavage. Numerous immature, soccer ball-like capsids were observed in cells harboring ORF29-deficient KSHV. The N-terminal region of ORF29 was important for its interaction with ORF7, although the full-length ORF29 was required for effective assembly of the KSHV terminase complex. Furthermore, ORF29 preferentially interacted with itself rather than with ORF7. Thus, our data show that ORF29 functions as a fundamental component of the terminase complex.IMPORTANCEBecause the role of ORF29 in the Kaposi's sarcoma-associated herpesvirus (KSHV) terminase complex remains unknown, we constructed ORF29-deficient KSHV. Our results demonstrated that ORF29 functions as a component of the KSHV terminase and is essential for mature capsid formation, terminal repeat (TR) cleavage, and terminase complex assembly. Moreover, ORF29 strongly interacted with itself. In herpes simplex virus 1 (HSV-1), the terminase complex (comprising UL15, UL28, and UL33) forms a trimer, and six such trimers assemble into a hexameric ring. The HSV-1 genome passes through this ring and undergoes TR cleavage and genome packaging into a capsid. The self-interaction of ORF29 may be involved in the multimerization of the terminase complex or in the formation of the KSHV terminase ring.

Herpesvirus 8, Human↗