PARP14 is regulated by the PARP9/DTX3L complex and promotes interferon γ-induced ADP-ribosylation

Author(s)

Ribeiro, Victoria Chaves ; Russo, Lilian Cristina ; Hoch, Nicolas Carlos

• Document type: Journal article
• Source: EMBO Journal; v. 43, n. 14, p. 21-pg., 2024-06-04.

Abstract

Protein ADP-ribosylation plays important but ill-defined roles in antiviral signalling cascades such as the interferon response. Several viruses of clinical interest, including coronaviruses, express hydrolases that reverse ADP-ribosylation catalysed by host enzymes, suggesting an important role for this modification in host-pathogen interactions. However, which ADP-ribosyltransferases mediate host ADP-ribosylation, what proteins and pathways they target and how these modifications affect viral infection and pathogenesis is currently unclear. Here we show that host ADP-ribosyltransferase activity induced by IFN gamma signalling depends on PARP14 catalytic activity and that the PARP9/DTX3L complex is required to uphold PARP14 protein levels via post-translational mechanisms. Both the PARP9/DTX3L complex and PARP14 localise to IFN gamma-induced cytoplasmic inclusions containing ADP-ribosylated proteins, and both PARP14 itself and DTX3L are likely targets of PARP14 ADP-ribosylation. We provide evidence that these modifications are hydrolysed by the SARS-CoV-2 Nsp3 macrodomain, shedding light on the intricate cross-regulation between IFN-induced ADP-ribosyltransferases and the potential roles of the coronavirus macrodomain in counteracting their activity. Protein ADP-ribosylation plays important but ill-defined roles in antiviral signaling cascades. This study demonstrates that PARP9, DTX3L and PARP14 regulate IFN gamma-induced ADP-ribosylation, and explores an intricate cross-regulation between these factors proposed to be targets of the coronavirus macrodomain.PARP14 catalytic activity is required for IFN gamma-induced ADP-ribosylation. PARP9 and DTX3L regulate PARP14 protein stability. PARP9, DTX3L, PARP14 and ADPr co-localize in IFN gamma-induced cytoplasmic structures. IFN gamma induces PARP14-dependent modification of itself and of DTX3L, which may be hydrolyzed by the SARS-CoV2 macrodomain. Interferon signaling induces cytoplasmic colocalization and cross-regulation of two ADP-ribosyltransferases and a ubiquitin ligase. (AU)

• FAPESP's process: 19/25914-1 - Role of PARP9/DTX3L-dependent H4K91 ubiquitination in the DNA damage response
• Grantee: Victoria Chaves Ribeiro
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 15/02654-3 - Multi-User Equipment approved in grant 2014/10492-0 fluorescence microscope
• Grantee: Alexandre Bruni Cardoso
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 20/11162-5 - Development of a cellular assay to measure SARS-CoV-2 Nsp3 macrodomain activity in vitro
• Grantee: Lilian Cristina Russo Vieira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/06039-2 - EMU awarded in the process 2018/18007-5: TissueFAXS microscope
• Grantee: Nicolas Carlos Hoch
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 22/10947-4 - Advanced technical support in cell biology and microscopy techniques
• Grantee: Lilian Cristina Russo Vieira
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 18/18007-5 - Protein ADP-ribosylation: DNA damage signalling and impacts on human health
• Grantee: Nicolas Carlos Hoch
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 23/15157-4 - Cellular roles of the PARP9/DTX3L heterodimer
• Grantee: Victoria Chaves Ribeiro
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 20/05317-6 - Inhibition of the viral macrodomain as a strategy for Coronavirus treatment
• Grantee: Nicolas Carlos Hoch
• Support Opportunities: Regular Research Grants