Human cytomegalovirus UL138 interaction with USP1 activates STAT1 in infection

Abstract

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 deubiquitinating 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 in infection 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.

MORC3 represses the HCMV major immediate early promoter in myeloid cells in the absence of PML nuclear bodies

“…Furthermore, we and others have shown that latent viral gene products regulate components of the innate immune system 37,[39][40][41][42] which may also serve to counteract this additional function of MORC3.…”

“…Whether the downregulation of MORC3 in the context of cellular differentiation is less clear—it is not reported that differentiating myeloid cells spontaneously start expressing IFN‐beta so this may be a moot point in the context of viral reactivation. Furthermore, we and others have shown that latent viral gene products regulate components of the innate immune system 37,39–42 which may also serve to counteract this additional function of MORC3.…”

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

“…We were struck by the similarity between the WT and Δ UL138 STOP viral transcriptomes, given the replicative phenotype in CD34 + HPCs where the Δ UL138 STOP recombinant produces similar numbers of infectious progeny both prior to and following reactivation stimulus, demonstrative of a loss of latency ( 27, 29, 30, 40 ). To further explore this, we analyzed Δ UL138 STOP infection in vivo using humanized mice (Figure 3A).…”

When DNA-damage responses meet innate and adaptive immunity

“…For instance, it has been discovered that USP1-associated factor 1 (UAF1) and ubiquitin-specific peptidase 1 (USP1) deubiquitinate the proteins FANCD2, FANCI, and PCNA to control DDR. The UAF1-USP1 association may be necessary for HCMV UL138 to control pSTAT1 for virus genomic latency, according to recent studies, raising the possibility that pSTAT may be an effector in virus infection-induced DNA damage [ 183 ].

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