Human Cytomegalovirus UL138 Protein Inhibits the STING Pathway and Reduces Interferon Beta mRNA Accumulation during Lytic and Latent Infections

Albright, Emily R.; Mickelson, Clayton K.; Kalejta, Robert F.

doi:10.1128/mbio.02267-21

Cited by 19 publications

(23 citation statements)

References 68 publications

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“…Contrary to our findings, Kalejta and colleagues showed that UL138 inhibits the innate immune response by targeting STING for degradation [41]. UL138 was shown to target STING, but this effect was only evident when both UL138 and STING were transiently overexpressed.…”

Section: Discussioncontrasting

confidence: 99%

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Human Cytomegalovirus UL138 Interaction with USP1 Activates STAT1 in infection

Zarrella

Longmire

Zeltzer

et al. 2023

Preprint

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Innate immune responses are crucial for limiting virus infection. However, viruses often hijack our best defenses for viral objectives. Human Cytomegalovirus (HCMV) is a beta herpesvirus which establishes a life-long latent infection. Defining the virus-host interactions controlling latency and reactivation is vital to the control of viral disease risk posed by virus reactivation. We defined an interaction between UL138, a pro-latency HCMV gene, and the host deubiquintase complex, UAF1-USP1. UAF1 is a scaffold protein pivotal for the activity of ubiquitin specific peptidases (USP), including USP1. UAF1-USP1 sustains an innate immune response through the phosphorylation and activation of signal transducer and activator of transcription-1 (pSTAT1), as well as regulates the DNA damage response. After the onset of viral DNA synthesis, pSTAT1 levels are elevated and this depends upon UL138 and USP1. pSTAT1 localizes to viral centers of replication, binds to the viral genome, and influences UL138 expression. Inhibition of USP1 results in a failure to establish latency, marked by increased viral genome replication and production of viral progeny. Inhibition of Jak-STAT signaling also results in increased viral genome synthesis in hematopoietic cells, consistent with a role for USP1-mediated regulation of STAT1 signaling in the establishment of latency. These findings demonstrate the importance of the UL138-UAF1-USP1 virus-host interaction in regulating HCMV latency establishment through the control of innate immune signaling. It will be important going forward to distinguish roles of UAF1-USP1 in regulating pSTAT1 relative to its role in the DNA damage response in HCMV infection.

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Section: Discussioncontrasting

confidence: 99%

“…Given the reported roles of USP1 in stabilizing TBK1 [40] and of UL138 in targeting STING for degradation outside the context of infection [41], we analyzed total and phosphorylated levels of TBK1 and STING during HCMV infection. Phosphorylated and total levels of TBK1 and STING remained unchanged between WT and Δ UL138 STOP infections (Fig.…”

Section: Resultsmentioning

confidence: 99%

Human Cytomegalovirus UL138 Interaction with USP1 Activates STAT1 in infection

Zarrella

Longmire

Zeltzer

et al. 2023

Preprint

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“…The remaining defects in virus production are indicative of the above mentioned complexity of mitochondrial alterations caused by mito-RFP-ER upon infection (Supplementary Fig. 10E ), and the possibility of STING performing both pro- and anti-viral roles during HCMV infections 6 , 85 , 95 . Together with our other findings that mito-ER tethering causes STING relocalization, TBK1 and IRF3 phosphorylation, cytokine secretion, reduced virus gene expression, and delayed infection onset, our results demonstrate that the STING immune pathway is a contributor to the anti-viral effect of premature ER-mitochondria tethering.…”

Section: Resultsmentioning

confidence: 99%

Restructured membrane contacts rewire organelles for human cytomegalovirus infection

et al. 2022

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Membrane contact sites (MCSs) link organelles to coordinate cellular functions across space and time. Although viruses remodel organelles for their replication cycles, MCSs remain largely unexplored during infections. Here, we design a targeted proteomics platform for measuring MCS proteins at all organelles simultaneously and define functional virus-driven MCS alterations by the ancient beta-herpesvirus human cytomegalovirus (HCMV). Integration with super-resolution microscopy and comparisons to herpes simplex virus (HSV-1), Influenza A, and beta-coronavirus HCoV-OC43 infections reveals time-sensitive contact regulation that allows switching anti- to pro-viral organelle functions. We uncover a stabilized mitochondria-ER encapsulation structure (MENC). As HCMV infection progresses, MENCs become the predominant mitochondria-ER contact phenotype and sequentially recruit the tethering partners VAP-B and PTPIP51, supporting virus production. However, premature ER-mitochondria tethering activates STING and interferon response, priming cells against infection. At peroxisomes, ACBD5-mediated ER contacts balance peroxisome proliferation versus membrane expansion, with ACBD5 impacting the titers of each virus tested.

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“…We and others have defined roles of UL133-138 gene locus encoded within the ULb' region of the HCMV genome for latency and reactivation. UL138 is required for latency and functions by regulating cell surface receptor trafficking and signaling (11)(12)(13)(14), innate immune responses (15) and also contributes to repression of viral gene expression (16). UL135, by contrast, is required for reactivation from latency, functioning in part by opposing the function of UL138 (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

LXR-inducible host E3 ligase IDOL targets a human cytomegalovirus reactivation determinant

Mlera

Zeltzer

Collins-McMillen

et al. 2022

Preprint

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Liver X receptor (LXR) signaling broadly restricts virus replication, however the mechanisms of restriction are poorly defined. Here, we demonstrate that the LXR-inducible cellular E3 ligase IDOL (inducible degrader of low-density lipoprotein receptor, LDLR) restricts replication of the beta-herpesvirus, human cytomegalovirus (HCMV), for the establishment of viral latency. IDOL is highly expressed in undifferentiated hematopoietic cells where HCMV establishes latency, but is sharply downregulated upon differentiation, a stimulus for reactivation. Importantly, IDOL restricts replication by driving the instability of a key viral determinant required for reactivation, the 33-kDa protein encoded by UL136 (UL136p33). UL136 encodes multiple proteins that differentially impact latency and reactivation. UL136p33 is targeted for rapid turnover by the proteasome and its stabilization by mutation of lysine residues to arginine results in a failure to quiet replication for latency. We show that IDOL interacts with and targets UL136p33 for turnover, but not the stabilized variant. While induction of IDOL prevents reactivation, IDOL depletion increases viral gene expression in undifferentiated hematopoietic cells. This work establishes the UL136p33-IDOL interaction as a key regulator of the bistable switch between latency and reactivation. It further implicates cholesterol homeostasis as a key determinant of HCMV reactivation whereby UL136p33 acts a sensor at the tipping point between the decision to maintain the latent state or exit latency for reactivation.

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Human Cytomegalovirus UL138 Protein Inhibits the STING Pathway and Reduces Interferon Beta mRNA Accumulation during Lytic and Latent Infections

Cited by 19 publications

References 68 publications

Human Cytomegalovirus UL138 Interaction with USP1 Activates STAT1 in infection

Human Cytomegalovirus UL138 Interaction with USP1 Activates STAT1 in infection

Restructured membrane contacts rewire organelles for human cytomegalovirus infection

LXR-inducible host E3 ligase IDOL targets a human cytomegalovirus reactivation determinant

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