Human cytomegalovirus UL138 interaction with USP1 activates STAT1 in infection.
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
06
02
2023
accepted:
30
05
2023
revised:
21
06
2023
medline:
23
6
2023
pubmed:
8
6
2023
entrez:
8
6
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37289831
doi: 10.1371/journal.ppat.1011185
pii: PPATHOGENS-D-23-00231
pmc: PMC10284425
doi:
Substances chimiques
Ubiquitin-Specific Proteases
EC 3.4.19.12
STAT1 protein, human
0
STAT1 Transcription Factor
0
USP1 protein, human
EC 3.4.19.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1011185Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM139779
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023074
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG058503
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
Copyright: © 2023 Zarrella et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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