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The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling

The Journal of biological chemistry, 2021-09, Vol.297 (3), p.101041-101041, Article 101041 [Peer Reviewed Journal]

2021 The Authors ;2021 The Authors 2021 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1016/j.jbc.2021.101041 ;PMID: 34358560

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  • Title:
    The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling
  • Author: Russo, Lilian Cristina ; Tomasin, Rebeka ; Matos, Isaac Araújo ; Manucci, Antonio Carlos ; Sowa, Sven T. ; Dale, Katie ; Caldecott, Keith W. ; Lehtiö, Lari ; Schechtman, Deborah ; Meotti, Flavia C. ; Bruni-Cardoso, Alexandre ; Hoch, Nicolas Carlos
  • Subjects: ADP-ribosylation ; COVID-19 ; DTX3L ; macrodomain ; PARP9 ; SARS-CoV-2
  • Is Part Of: The Journal of biological chemistry, 2021-09, Vol.297 (3), p.101041-101041, Article 101041
  • Description: SARS-CoV-2 nonstructural protein 3 (Nsp3) contains a macrodomain that is essential for coronavirus pathogenesis and is thus an attractive target for drug development. This macrodomain is thought to counteract the host interferon (IFN) response, an important antiviral signalling cascade, via the reversal of protein ADP-ribosylation, a posttranslational modification catalyzed by host poly(ADP-ribose) polymerases (PARPs). However, the main cellular targets of the coronavirus macrodomain that mediate this effect are currently unknown. Here, we use a robust immunofluorescence-based assay to show that activation of the IFN response induces ADP-ribosylation of host proteins and that ectopic expression of the SARS-CoV-2 Nsp3 macrodomain reverses this modification in human cells. We further demonstrate that this assay can be used to screen for on-target and cell-active macrodomain inhibitors. This IFN-induced ADP-ribosylation is dependent on PARP9 and its binding partner DTX3L, but surprisingly the expression of the Nsp3 macrodomain or the deletion of either PARP9 or DTX3L does not impair IFN signaling or the induction of IFN-responsive genes. Our results suggest that PARP9/DTX3L-dependent ADP-ribosylation is a downstream effector of the host IFN response and that the cellular function of the SARS-CoV-2 Nsp3 macrodomain is to hydrolyze this end product of IFN signaling, rather than to suppress the IFN response itself.
  • Publisher: Elsevier Inc
  • Language: English
  • Identifier: ISSN: 0021-9258
    EISSN: 1083-351X
    DOI: 10.1016/j.jbc.2021.101041
    PMID: 34358560
  • Source: PubMed Central
    Alma/SFX Local Collection
    DOAJ Directory of Open Access Journals
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