The Human Cytomegalovirus Tegument Protein pp65 (pUL83) Dampens Type I Interferon Production by Inactivating the DNA Sensor cGAS without Affecting STING

Publikation: Forskning - peer reviewTidsskriftartikel

DOI

  • Matteo Biolatti
    Matteo BiolattiDepartment of Public Health and Pediatric Sciences, University of Turin, Turin, Italy.
  • Valentina Dell'Oste
    Valentina Dell'OsteDepartment of Public Health and Pediatric Sciences, University of Turin, Turin, Italy.
  • Sara Pautasso
    Sara PautassoDepartment of Public Health and Pediatric Sciences, University of Turin, Turin, Italy.
  • Francesca Gugliesi
    Francesca GugliesiDepartment of Public Health and Pediatric Sciences, University of Turin, Turin, Italy.
  • Jens von Einem
    Jens von EinemUlm University Medical Center, Institute of Molecular Virology, Meyerhofstr. 1, Ulm 89081, Germany.
  • Christian Krapp
  • Martin Roelsgaard Jakobsen
  • Cinzia Borgogna
    Cinzia BorgognaDepartment of Translational Medicine, Novara Medical School, Novara, Italy.
  • Marisa Gariglio
    Marisa GariglioDepartment of Translational Medicine, Novara Medical School, Novara, Italy.
  • Marco De Andrea
    Marco De AndreaDepartment of Translational Medicine, Novara Medical School, Novara, Italy.
  • Santo Landolfo
    Santo LandolfoDepartment of Public Health and Pediatric Sciences, University of Turin, Turin, Italy santo.landolfo@unito.it.

The innate immune response plays a pivotal role during human cytomegalovirus (HCMV) primary infection. Indeed, HCMV infection of primary fibroblasts rapidly triggers strong induction of type I interferons (IFN-I) accompanied by proinflammatory cytokine release. Here, we show that primary human foreskin fibroblasts (HFFs) infected with a mutant HCMV TB40/E strain unable to express UL83-encoded pp65 (v65Stop) produce significantly higher IFN-β levels than HFFs infected with the wild-type TB40/E strain or the pp65 revertant (v65Rev), suggesting that the tegument protein pp65 may dampen IFN-β production. To clarify the mechanisms through which pp65 inhibits IFN-β production, we analyzed the activation of the cGAS/STING/IRF3 axis in HFFs infected with either wild-type, v65Rev or the pp65-deficient mutant v65Stop. We found that pp65 selectively binds to cGAS and prevents its interaction with STING, thus inactivating the signaling pathway through the cGAS/STING/IRF3 axis. Consistently, addition of exogenous cGAMP to v65Rev infected cells triggered the production of IFN-β levels similar to those observed with v65Stop infected cells confirming that pp65 inactivation of IFN-β production occurs at the cGAS level. Notably, within the first 24 hours of HCMV infection, STING undergoes proteasome degradation independent of the presence or absence of pp65. Collectively, our data provide mechanistic insights into the interplay between HCMV pp65 and cGAS, leading to subsequent immune evasion by this prominent DNA virus.IMPORTANCE Primary human foreskin fibroblasts (HFFs) produce type I IFN (IFN-I) when infected with HCMV. However, we observed significantly higher IFN-β levels when HFFs were infected with HCMV unable to express UL83-encoded pp65 (v65Stop), suggesting that pp65 (pUL83) may constitute a viral evasion factor. This study demonstrates that HCMV tegument protein pp65 inhibits IFN-β production by binding and inactivating cGAS early during infection. In addition, this inhibitory activity specifically targets cGAS since it can be bypassed via the addition of exogenous cGAMP, even in presence of pp65. Notably, STING proteasome-mediated degradation was observed in both the presence and absence of pp65. Collectively, our data underscore the important role of tegument protein pp65 as a critical molecular hub in HCMV's evasion strategy to the innate immune response.

OriginalsprogEngelsk
TidsskriftJournal of Virology
ISSN0022-538X
DOI
StatusUdgivet - dec. 2017

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