UL135 and UL136 Epistasis Controls Reactivation of Human Cytomegalovirus

Moy, Melissa; Collins-McMillen, Donna; Crawford, Lindsey B.; Parkins, Chrisopher; Zeltzer, Sebastian; Caviness, Katie; Caposio, Patrizia; Goodrum, Felicia

doi:10.1101/2023.01.24.525282

Cited by 6 publications

(3 citation statements)

References 90 publications

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“…The UL133-UL138 latency locus encodes at least four proteins that modulate viral replication to promote latency or reactivation, and these are among the eleven genes that are dependent on pUL135 for their re-expression following reactivation stimulus. The discovery of pUL135 as a driver of gene expression from the UL133-UL138 locus is consistent with our previous work showing that the 33 kDa isoform of pUL136 is important for driving reactivation from latency (50,51) and that stabilization of this isoform overcomes the requirement for pUL135 in promoting viral replication in hematopoietic cells (52).…”

Section: Motif Analysis Reveals Candidate Transcription Factors For C...supporting

confidence: 91%

Viral and host network analysis of the human cytomegalovirus transcriptome in latency

Collins-McMillen,

Oliveira Pessoa,

Zarrella

et al. 2024

Preprint

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HCMV genes UL135 and UL138 play opposing roles regulating latency and reactivation in CD34+ human progenitor cells (HPCs). Using the THP-1 cell line model for latency and reactivation, we designed an RNA sequencing study to compare the transcriptional profile of HCMV infection in the presence and absence of these genes. The loss of UL138 results in elevated levels of viral gene expression and increased differentiation of cell populations that support HCMV gene expression and genome synthesis. The loss of UL135 results in diminished viral gene expression during an initial burst that occurs as latency is established and no expression of eleven viral genes from the ULb′ region even following stimulation for differentiation and reactivation. Transcriptional network analysis revealed host transcription factors with potential to regulate the ULb′ genes in coordination with pUL135. These results reveal roles for UL135 and UL138 in regulation of viral gene expression and potentially hematopoietic differentiation.

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Section: Motif Analysis Reveals Candidate Transcription Factors For C...supporting

confidence: 91%

Viral and host network analysis of the human cytomegalovirus transcriptome in latency

Collins-McMillen,

Oliveira Pessoa,

Zarrella

et al. 2024

Preprint

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“…Moreover, HCMV proteins, such as UL138 and UL135, that regulate EGFR-a key upstream modulator of PI3K/AKT, play pivotal yet opposing roles in maintenance of latency [44,89]. Because HCMV must render AKT inactive to efficiently replicate [42], UL38 likely plays a major role in the latent-lytic switch.…”

Section: Discussionmentioning

confidence: 99%

Human cytomegalovirus attenuates AKT activity by destabilizing insulin receptor substrate proteins

Domma

Goodrum

Moorman

et al. 2023

Preprint

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The phosphoinositide 3-kinase (PI3K)/AKT pathway plays crucial roles in cell viability and protein synthesis and is frequently co-opted by viruses to support their replication. Although many viruses maintain high levels of AKT activity during infection, other viruses, such as vesicular stomatitis virus and human cytomegalovirus (HCMV), cause AKT to accumulate in an inactive state. To efficiently replicate, HCMV requires FoxO transcription factors to localize to the infected cell nucleus (Zhang et. al. mBio 2022), a process directly antagonized by AKT. Therefore, we sought to investigate how HCMV inactivates AKT to achieve this. Subcellular fractionation and live cell imaging studies indicated that AKT failed to recruit to membranes upon serum-stimulation of infected cells. However, UV-inactivated virions were unable to render AKT non-responsive to serum, indicating a requirement for de novo viral gene expression. Interestingly, we were able to identify that UL38 (pUL38), a viral activator of mTORC1, is required to diminish AKT responsiveness to serum. mTORC1 contributes to insulin resistance by causing proteasomal degradation of insulin receptor substrate (IRS) proteins, such as IRS1, which are necessary for the recruitment of PI3K to growth factor receptors. In cells infected with a recombinant HCMV disrupted for UL38, AKT responsiveness to serum is retained and IRS1 is not degraded. Furthermore, ectopic expression of UL38 in uninfected cells induces IRS1 degradation, inactivating AKT. These effects of UL38 were reversed by the mTORC1 inhibitor, rapamycin. Collectively, our results demonstrate that HCMV relies upon a cell-intrinsic negative feedback loop to render AKT inactive during productive infection.

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“…Promotes viral gene expression [438]; Regulates EGFR and reactivation [427,439,440] Immune evasion [65,437] [446,447];…”

Section: Ul138mentioning

confidence: 99%

Insights into the Transcriptome of Human Cytomegalovirus: A Comprehensive Review

Zeng

Cao

Yang

et al. 2023

Viruses

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Human cytomegalovirus (HCMV) is a widespread pathogen that poses significant risks to immunocompromised individuals. Its genome spans over 230 kbp and potentially encodes over 200 open-reading frames. The HCMV transcriptome consists of various types of RNAs, including messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs), with emerging insights into their biological functions. HCMV mRNAs are involved in crucial viral processes, such as viral replication, transcription, and translation regulation, as well as immune modulation and other effects on host cells. Additionally, four lncRNAs (RNA1.2, RNA2.7, RNA4.9, and RNA5.0) have been identified in HCMV, which play important roles in lytic replication like bypassing acute antiviral responses, promoting cell movement and viral spread, and maintaining HCMV latency. CircRNAs have gained attention for their important and diverse biological functions, including association with different diseases, acting as microRNA sponges, regulating parental gene expression, and serving as translation templates. Remarkably, HCMV encodes miRNAs which play critical roles in silencing human genes and other functions. This review gives an overview of human cytomegalovirus and current research on the HCMV transcriptome during lytic and latent infection.

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UL135 and UL136 Epistasis Controls Reactivation of Human Cytomegalovirus

Cited by 6 publications

References 90 publications

Viral and host network analysis of the human cytomegalovirus transcriptome in latency

Viral and host network analysis of the human cytomegalovirus transcriptome in latency

Human cytomegalovirus attenuates AKT activity by destabilizing insulin receptor substrate proteins

Insights into the Transcriptome of Human Cytomegalovirus: A Comprehensive Review

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